Vaccines

(Reuters) -A top U.S. health official on Monday called for the combined measles-mumps-rubella shot to be broken up, drawing a quick rebuke from vaccine maker Merck, which said there is no scientific evidence that shows any benefit to doing so.

The U.S. CDC earlier on Monday pulled broad support for COVID-19 shots, saying they should be administered through shared decision-making with a health care provider in accordance with recommendations from Health Secretary Robert F. Kennedy Jr.’s hand-picked vaccine advisory panel.

The acting director of the Centers for Disease Control and Prevention, Jim O’Neill, in an X post on Monday called on vaccine manufacturers to develop three separate vaccines to replace the combined MMR inoculation.

In a September 23 news conference at the White House, President Donald Trump delivered medical advice to pregnant women and parents of young children, repeatedly telling them common vaccines should not be taken together or so early in a child’s life, and urging them not to use or administer Tylenol, against the advice of medical societies.

Kennedy, a long-time anti-vaccine crusader before taking on the nation’s top health post, has linked vaccines to autism and sought to rewrite the country’s immunization policies. He fired all members of the national vaccine advisory board of outside experts and replaced them with new members, many of whom shared his views. The committee is reviewing the childhood vaccine schedule.

The causes of autism are unclear. But no rigorous studies have found links between autism and vaccines or medications, or their components such as thimerosal or formaldehyde. Vaccination rates have declined as autism rates have climbed.

 

MERCK, EXPERTS DEFEND MMR SHOT

Merck said there is no published scientific evidence that shows any benefit in separating the MMR shot. 

According to the U.S. Food and Drug Administration’s website, there are currently no separate single virus shots for measles, mumps or rubella licensed for use in the United States. That means manufacturers could need to go through the FDA approval process before any become available.

“Use of the individual components of combination vaccines increases the number of injections for the individual and may result in delayed or missed immunizations,” Merck said in a statement.

Dr. Rana Alissa, president of the Florida chapter of the American Academy of Pediatrics, said the purpose of combining the three shots in the MMR vaccine is not only to save parents extra visits to the doctor’s office.

“Studies have shown that when you give them together, the immune response is much better,” she said. “This is how you get lifelong immunity.”

GSK, which also makes an MMR shot, declined to comment. A spokesman for the U.S. Department of Health and Human Services, where O’Neill is deputy secretary, was not immediately available for comment.

The break-up of the MMR shot would “falsely imply that there is something unsafe about giving the measles, mumps, and rubella vaccines at the same time,” said Dr. Amesh Adalja, an infectious disease expert at the Johns Hopkins Center for Health Security. 

“It would be another example of the federal government pandering to the anti-vaccine movement,” Adalja added.

Earlier in the day, the CDC signed off on the advisers’ recommendations against use of the combined measles-mumps-rubella-varicella vaccine before the age of 4 years because of a slight risk of seizures related to high fevers. Instead, varicella, commonly known as chickenpox, is recommended as a standalone shot.

Merck also makes the measles-mumps-rubella-varicella shot.

CDC CHANGES COVID VIEWS      

The new CDC recommendation on the COVID vaccine calls for physician involvement but maintains access for the shot through health insurance.

The immunization schedules will be updated on the CDC website by Tuesday, the agency said.

The recommendations come after upheaval at the CDC, including the ouster of its former Director Susan Monarez, who had resisted changes to vaccine policy advanced by Kennedy. Monarez said she was told to rubber-stamp the committee’s recommendations without reviewing the scientific evidence. 

The new advisory panel made its recommendations at a two-day meeting in September that highlighted deep divisions over the future of the U.S. immunization schedules under Kennedy.

The American Academy of Pediatrics, an influential U.S. medical group, has already broken from federal policy and pushed its own vaccine recommendations, suggesting all young children get vaccinated against COVID-19.

The U.S. Food and Drug Administration in August cleared updated COVID-19 vaccines for everyone over age 65, but limited its approval for younger people to those with health risks.

The 3 approved COVID shots are made by Pfizer with German partner BioNTech, Moderna, and Novavax with Sanofi.

(Reporting by Mariam Sunny in Bengaluru, Michael Erman in New York and Julie Steenhuysen in Chicago; Editing by Caroline Humer and Bill Berkrot)■

A version of this article appeared on Medscape.com.

(Reuters) -A top U.S. health official on Monday called for the combined measles-mumps-rubella shot to be broken up, drawing a quick rebuke from vaccine maker Merck, which said there is no scientific evidence that shows any benefit to doing so.

The U.S. CDC earlier on Monday pulled broad support for COVID-19 shots, saying they should be administered through shared decision-making with a health care provider in accordance with recommendations from Health Secretary Robert F. Kennedy Jr.’s hand-picked vaccine advisory panel.

The acting director of the Centers for Disease Control and Prevention, Jim O’Neill, in an X post on Monday called on vaccine manufacturers to develop three separate vaccines to replace the combined MMR inoculation.

In a September 23 news conference at the White House, President Donald Trump delivered medical advice to pregnant women and parents of young children, repeatedly telling them common vaccines should not be taken together or so early in a child’s life, and urging them not to use or administer Tylenol, against the advice of medical societies.

Kennedy, a long-time anti-vaccine crusader before taking on the nation’s top health post, has linked vaccines to autism and sought to rewrite the country’s immunization policies. He fired all members of the national vaccine advisory board of outside experts and replaced them with new members, many of whom shared his views. The committee is reviewing the childhood vaccine schedule.

The causes of autism are unclear. But no rigorous studies have found links between autism and vaccines or medications, or their components such as thimerosal or formaldehyde. Vaccination rates have declined as autism rates have climbed.

 

MERCK, EXPERTS DEFEND MMR SHOT

Merck said there is no published scientific evidence that shows any benefit in separating the MMR shot. 

According to the U.S. Food and Drug Administration’s website, there are currently no separate single virus shots for measles, mumps or rubella licensed for use in the United States. That means manufacturers could need to go through the FDA approval process before any become available.

“Use of the individual components of combination vaccines increases the number of injections for the individual and may result in delayed or missed immunizations,” Merck said in a statement.

Dr. Rana Alissa, president of the Florida chapter of the American Academy of Pediatrics, said the purpose of combining the three shots in the MMR vaccine is not only to save parents extra visits to the doctor’s office.

“Studies have shown that when you give them together, the immune response is much better,” she said. “This is how you get lifelong immunity.”

GSK, which also makes an MMR shot, declined to comment. A spokesman for the U.S. Department of Health and Human Services, where O’Neill is deputy secretary, was not immediately available for comment.

The break-up of the MMR shot would “falsely imply that there is something unsafe about giving the measles, mumps, and rubella vaccines at the same time,” said Dr. Amesh Adalja, an infectious disease expert at the Johns Hopkins Center for Health Security. 

“It would be another example of the federal government pandering to the anti-vaccine movement,” Adalja added.

Earlier in the day, the CDC signed off on the advisers’ recommendations against use of the combined measles-mumps-rubella-varicella vaccine before the age of 4 years because of a slight risk of seizures related to high fevers. Instead, varicella, commonly known as chickenpox, is recommended as a standalone shot.

Merck also makes the measles-mumps-rubella-varicella shot.

CDC CHANGES COVID VIEWS      

The new CDC recommendation on the COVID vaccine calls for physician involvement but maintains access for the shot through health insurance.

The immunization schedules will be updated on the CDC website by Tuesday, the agency said.

The recommendations come after upheaval at the CDC, including the ouster of its former Director Susan Monarez, who had resisted changes to vaccine policy advanced by Kennedy. Monarez said she was told to rubber-stamp the committee’s recommendations without reviewing the scientific evidence. 

The new advisory panel made its recommendations at a two-day meeting in September that highlighted deep divisions over the future of the U.S. immunization schedules under Kennedy.

The American Academy of Pediatrics, an influential U.S. medical group, has already broken from federal policy and pushed its own vaccine recommendations, suggesting all young children get vaccinated against COVID-19.

The U.S. Food and Drug Administration in August cleared updated COVID-19 vaccines for everyone over age 65, but limited its approval for younger people to those with health risks.

The 3 approved COVID shots are made by Pfizer with German partner BioNTech, Moderna, and Novavax with Sanofi.

(Reporting by Mariam Sunny in Bengaluru, Michael Erman in New York and Julie Steenhuysen in Chicago; Editing by Caroline Humer and Bill Berkrot)■

A version of this article appeared on Medscape.com.

(Reuters) -A top U.S. health official on Monday called for the combined measles-mumps-rubella shot to be broken up, drawing a quick rebuke from vaccine maker Merck, which said there is no scientific evidence that shows any benefit to doing so.

The U.S. CDC earlier on Monday pulled broad support for COVID-19 shots, saying they should be administered through shared decision-making with a health care provider in accordance with recommendations from Health Secretary Robert F. Kennedy Jr.’s hand-picked vaccine advisory panel.

The acting director of the Centers for Disease Control and Prevention, Jim O’Neill, in an X post on Monday called on vaccine manufacturers to develop three separate vaccines to replace the combined MMR inoculation.

In a September 23 news conference at the White House, President Donald Trump delivered medical advice to pregnant women and parents of young children, repeatedly telling them common vaccines should not be taken together or so early in a child’s life, and urging them not to use or administer Tylenol, against the advice of medical societies.

Kennedy, a long-time anti-vaccine crusader before taking on the nation’s top health post, has linked vaccines to autism and sought to rewrite the country’s immunization policies. He fired all members of the national vaccine advisory board of outside experts and replaced them with new members, many of whom shared his views. The committee is reviewing the childhood vaccine schedule.

The causes of autism are unclear. But no rigorous studies have found links between autism and vaccines or medications, or their components such as thimerosal or formaldehyde. Vaccination rates have declined as autism rates have climbed.

 

MERCK, EXPERTS DEFEND MMR SHOT

Merck said there is no published scientific evidence that shows any benefit in separating the MMR shot. 

According to the U.S. Food and Drug Administration’s website, there are currently no separate single virus shots for measles, mumps or rubella licensed for use in the United States. That means manufacturers could need to go through the FDA approval process before any become available.

“Use of the individual components of combination vaccines increases the number of injections for the individual and may result in delayed or missed immunizations,” Merck said in a statement.

Dr. Rana Alissa, president of the Florida chapter of the American Academy of Pediatrics, said the purpose of combining the three shots in the MMR vaccine is not only to save parents extra visits to the doctor’s office.

“Studies have shown that when you give them together, the immune response is much better,” she said. “This is how you get lifelong immunity.”

GSK, which also makes an MMR shot, declined to comment. A spokesman for the U.S. Department of Health and Human Services, where O’Neill is deputy secretary, was not immediately available for comment.

The break-up of the MMR shot would “falsely imply that there is something unsafe about giving the measles, mumps, and rubella vaccines at the same time,” said Dr. Amesh Adalja, an infectious disease expert at the Johns Hopkins Center for Health Security. 

“It would be another example of the federal government pandering to the anti-vaccine movement,” Adalja added.

Earlier in the day, the CDC signed off on the advisers’ recommendations against use of the combined measles-mumps-rubella-varicella vaccine before the age of 4 years because of a slight risk of seizures related to high fevers. Instead, varicella, commonly known as chickenpox, is recommended as a standalone shot.

Merck also makes the measles-mumps-rubella-varicella shot.

CDC CHANGES COVID VIEWS      

The new CDC recommendation on the COVID vaccine calls for physician involvement but maintains access for the shot through health insurance.

The immunization schedules will be updated on the CDC website by Tuesday, the agency said.

The recommendations come after upheaval at the CDC, including the ouster of its former Director Susan Monarez, who had resisted changes to vaccine policy advanced by Kennedy. Monarez said she was told to rubber-stamp the committee’s recommendations without reviewing the scientific evidence. 

The new advisory panel made its recommendations at a two-day meeting in September that highlighted deep divisions over the future of the U.S. immunization schedules under Kennedy.

The American Academy of Pediatrics, an influential U.S. medical group, has already broken from federal policy and pushed its own vaccine recommendations, suggesting all young children get vaccinated against COVID-19.

The U.S. Food and Drug Administration in August cleared updated COVID-19 vaccines for everyone over age 65, but limited its approval for younger people to those with health risks.

The 3 approved COVID shots are made by Pfizer with German partner BioNTech, Moderna, and Novavax with Sanofi.

(Reporting by Mariam Sunny in Bengaluru, Michael Erman in New York and Julie Steenhuysen in Chicago; Editing by Caroline Humer and Bill Berkrot)■

A version of this article appeared on Medscape.com.

TOPLINE: Human Papillomavirus (HPV) vaccination is associated with reduced risks of rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes among females aged 9 to 45 years. The analysis of 208,638 vaccinated individuals shows particularly strong protective effects in those aged 9 to 26 years and recipients of 9-valent HPV vaccines.

METHODOLOGY:

• Researchers analyzed data from the US Collaborative Network in TriNetX spanning January 1, 2018, to December 20, 2022, enrolling 208,638 females aged 9 to 45 years who received HPV vaccination and matching them with 208,638 unvaccinated individuals using propensity scores.

• Analysis included Cox proportional hazard regression to estimate hazard ratios and 95% CIs for immune-mediated diseases, with subgroup analyses stratified by age, race, smoking, obesity, asthma, and HPV vaccine types.

• Participants were monitored from 31 days up to 365 days following their respective index dates, with sensitivity analyses conducted to evaluate short-term outcomes and compare results with influenza virus vaccine recipients.

TAKEAWAY:

• HPV vaccination demonstrated reduced risks for rheumatoid arthritis (hazard ratio [HR], 0.487; 95% confidence interval [CI], 0.311-0.762), systemic lupus erythematosus (HR, 0.287; 95% CI, 0.179-0.460), and dermatomyositis (HR, 0.299; 95% CI, 0.098-0.908).

• Recipients showed lower risks for inflammatory bowel disease (HR, 0.876; 95% CI, 0.811-0.946), celiac disease (HR, 0.400; 95% CI, 0.304-0.526), and type 1 diabetes (HR, 0.242; 95% CI, 0.184-0.318).

• Subgroup analyses revealed significant risk reductions among females aged 9 to 26 years and those receiving 9-valent HPV vaccines compared to unvaccinated populations.

• White and Black/African American individuals demonstrated reduced risks for various immune-mediated diseases, while Asians showed lower risks only for inflammatory bowel disease and overall immune-mediated diseases.

 IN PRACTICE: "Our real-world investigation employing TriNetX Research Network has revealed a significant reduction in the risks of various immune-mediated diseases, especially among females aged 9-26 years and those who received 9-valent HPV vaccines,” the author wrote.

SOURCE: The study was led by Qianru Zhang, MD, Beijing Tsinghua Changgung Hospital in Beijing, China, James Cheng-Chung Wei, and Shiow-Ing Wang who contributed equally as first authors. It was published online in QJM: An International Journal of Medicine.

LIMITATIONS:  According to the authors, research relying on Electronic Health Records (EHR) faced several constraints, including the absence of serial data on HPV antibody titers in vaccinated individuals and limited data regarding vaccination dosing numbers. Additionally, the current functionality of TriNetX prevented performing interaction terms in the statistical model for comprehensive subgroup analysis stratified by age, race, and vaccine types.

DISCLOSURES: The study received support from Chung Shan Medical University Hospital (Grant No. CSH-2023-E-001-Y2), Kaohsiung Veterans General Hospital (KSVGH 113-117), National Science and Technology Council (NSTC 112-2314-B-075B-020), and KSVNSU112-008. The funders had no role in the study's design, conduct, data analysis, or manuscript approval.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Human Papillomavirus (HPV) vaccination is associated with reduced risks of rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes among females aged 9 to 45 years. The analysis of 208,638 vaccinated individuals shows particularly strong protective effects in those aged 9 to 26 years and recipients of 9-valent HPV vaccines.

METHODOLOGY:

• Researchers analyzed data from the US Collaborative Network in TriNetX spanning January 1, 2018, to December 20, 2022, enrolling 208,638 females aged 9 to 45 years who received HPV vaccination and matching them with 208,638 unvaccinated individuals using propensity scores.

• Analysis included Cox proportional hazard regression to estimate hazard ratios and 95% CIs for immune-mediated diseases, with subgroup analyses stratified by age, race, smoking, obesity, asthma, and HPV vaccine types.

• Participants were monitored from 31 days up to 365 days following their respective index dates, with sensitivity analyses conducted to evaluate short-term outcomes and compare results with influenza virus vaccine recipients.

TAKEAWAY:

• HPV vaccination demonstrated reduced risks for rheumatoid arthritis (hazard ratio [HR], 0.487; 95% confidence interval [CI], 0.311-0.762), systemic lupus erythematosus (HR, 0.287; 95% CI, 0.179-0.460), and dermatomyositis (HR, 0.299; 95% CI, 0.098-0.908).

• Recipients showed lower risks for inflammatory bowel disease (HR, 0.876; 95% CI, 0.811-0.946), celiac disease (HR, 0.400; 95% CI, 0.304-0.526), and type 1 diabetes (HR, 0.242; 95% CI, 0.184-0.318).

• Subgroup analyses revealed significant risk reductions among females aged 9 to 26 years and those receiving 9-valent HPV vaccines compared to unvaccinated populations.

• White and Black/African American individuals demonstrated reduced risks for various immune-mediated diseases, while Asians showed lower risks only for inflammatory bowel disease and overall immune-mediated diseases.

 IN PRACTICE: "Our real-world investigation employing TriNetX Research Network has revealed a significant reduction in the risks of various immune-mediated diseases, especially among females aged 9-26 years and those who received 9-valent HPV vaccines,” the author wrote.

SOURCE: The study was led by Qianru Zhang, MD, Beijing Tsinghua Changgung Hospital in Beijing, China, James Cheng-Chung Wei, and Shiow-Ing Wang who contributed equally as first authors. It was published online in QJM: An International Journal of Medicine.

LIMITATIONS:  According to the authors, research relying on Electronic Health Records (EHR) faced several constraints, including the absence of serial data on HPV antibody titers in vaccinated individuals and limited data regarding vaccination dosing numbers. Additionally, the current functionality of TriNetX prevented performing interaction terms in the statistical model for comprehensive subgroup analysis stratified by age, race, and vaccine types.

DISCLOSURES: The study received support from Chung Shan Medical University Hospital (Grant No. CSH-2023-E-001-Y2), Kaohsiung Veterans General Hospital (KSVGH 113-117), National Science and Technology Council (NSTC 112-2314-B-075B-020), and KSVNSU112-008. The funders had no role in the study's design, conduct, data analysis, or manuscript approval.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Human Papillomavirus (HPV) vaccination is associated with reduced risks of rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes among females aged 9 to 45 years. The analysis of 208,638 vaccinated individuals shows particularly strong protective effects in those aged 9 to 26 years and recipients of 9-valent HPV vaccines.

METHODOLOGY:

• Researchers analyzed data from the US Collaborative Network in TriNetX spanning January 1, 2018, to December 20, 2022, enrolling 208,638 females aged 9 to 45 years who received HPV vaccination and matching them with 208,638 unvaccinated individuals using propensity scores.

• Analysis included Cox proportional hazard regression to estimate hazard ratios and 95% CIs for immune-mediated diseases, with subgroup analyses stratified by age, race, smoking, obesity, asthma, and HPV vaccine types.

• Participants were monitored from 31 days up to 365 days following their respective index dates, with sensitivity analyses conducted to evaluate short-term outcomes and compare results with influenza virus vaccine recipients.

TAKEAWAY:

• HPV vaccination demonstrated reduced risks for rheumatoid arthritis (hazard ratio [HR], 0.487; 95% confidence interval [CI], 0.311-0.762), systemic lupus erythematosus (HR, 0.287; 95% CI, 0.179-0.460), and dermatomyositis (HR, 0.299; 95% CI, 0.098-0.908).

• Recipients showed lower risks for inflammatory bowel disease (HR, 0.876; 95% CI, 0.811-0.946), celiac disease (HR, 0.400; 95% CI, 0.304-0.526), and type 1 diabetes (HR, 0.242; 95% CI, 0.184-0.318).

• Subgroup analyses revealed significant risk reductions among females aged 9 to 26 years and those receiving 9-valent HPV vaccines compared to unvaccinated populations.

• White and Black/African American individuals demonstrated reduced risks for various immune-mediated diseases, while Asians showed lower risks only for inflammatory bowel disease and overall immune-mediated diseases.

 IN PRACTICE: "Our real-world investigation employing TriNetX Research Network has revealed a significant reduction in the risks of various immune-mediated diseases, especially among females aged 9-26 years and those who received 9-valent HPV vaccines,” the author wrote.

SOURCE: The study was led by Qianru Zhang, MD, Beijing Tsinghua Changgung Hospital in Beijing, China, James Cheng-Chung Wei, and Shiow-Ing Wang who contributed equally as first authors. It was published online in QJM: An International Journal of Medicine.

LIMITATIONS:  According to the authors, research relying on Electronic Health Records (EHR) faced several constraints, including the absence of serial data on HPV antibody titers in vaccinated individuals and limited data regarding vaccination dosing numbers. Additionally, the current functionality of TriNetX prevented performing interaction terms in the statistical model for comprehensive subgroup analysis stratified by age, race, and vaccine types.

DISCLOSURES: The study received support from Chung Shan Medical University Hospital (Grant No. CSH-2023-E-001-Y2), Kaohsiung Veterans General Hospital (KSVGH 113-117), National Science and Technology Council (NSTC 112-2314-B-075B-020), and KSVNSU112-008. The funders had no role in the study's design, conduct, data analysis, or manuscript approval.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A mid-season analysis of the influenza vaccine by the US Department of Defensive (DoD) Global Respiratory Pathogen Surveillance Program (DoDGRPSP) has reported low to moderate vaccine effectiveness (VE). 

The study included 295 Military Health System (MHS) beneficiaries (adults and children) who tested positive for influenza and 965 controls who tested negative. Vaccinated patients had received the 2024-2025 influenza vaccine at least 14 days prior to symptom onset. The study conducted VE analyses for influenza A (any subtype), influenza A(H1N1)pdm09, and influenza A(H3N2). 

Overall, moderate effectiveness against influenza A(H1N1)pdm09 was reported in all beneficiaries and children aged 6 months to 17 years. In adults aged 18 to 64 years—and all beneficiaries—there was moderate effectiveness against influenza A(H3N2). VE estimates against influenza A (any subtype) for all beneficiaries, children, and adults were not significant; VE estimates were also not effective among children for influenza A(H3N2) and in adults for influenza A(H1N1)pdm09.

Adjusted VE estimates among all participants for influenza A (any subtypes), influenza A(H1N1)pdm09, and influenza A(H3N2) were 25%, 58%, and 42%, respectively. VE for influenza B was not calculated due to a low number of cases.

Flu vaccination rates for adults are usually in the 30% to 60% range despite the recommended target of 70%. Flu vaccination rates were rising by around 1% to 2% annually before 2020, but began dropping after the COVID-19 pandemic, especially in higher-risk groups. In adults aged ≥ 65 years, flu vaccination rates dropped from 52% in 2019-2020 to 43% in 2024-2025.

According to the Centers for Disease Control and Prevention (CDC), at the end of the 2023-2024 flu season, 9.2 million fewer doses were administered in pharmacies and doctors offices compared with the baseline before the COVID-19 pandemic. Since 2022, private manufacturers have distributed significantly fewer influenza vaccine doses. 

Each March, the US Food and Drug Association (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) meets to analyze the current influenza season and forecast the next. The committee reviews and discusses data on influenza strain circulation and VE, which come from DoDGRPSP analyses. In February, US Department of Health and Human Services officials indefinitely postponed a public meeting of the CDC Advisory Committee on Immunization Practice (ACIP), at which members were also expected to discuss, among other things, VE and vaccine recommendations. The FDA canceled a March 13 VRBPAC meeting and provided no reason for the cancelation to members. That day, however, the FDA issued new recommendations for the influenza vaccine for the 2025-2026 season without the input of VRBPAC. Instead, experts from the FDA, CDC, and DoD made recommendations after reviewing surveillance data from the US and globally.

For the 2025-2026 influenza season, the FDA recommends the vaccines be trivalent and target 2 strains of influenza A and 1 strain of influenza B. The FDA anticipates there will be an “adequate and diverse supply” of approved trivalent seasonal influenza vaccines. Trivalent flu vaccines are formulated to protect against 3 influenza viruses: an A(H1N1) virus, an A(H3N2) virus, and a B/Victoria virus. All influenza vaccines for the 2025-2026 season are anticipated to be trivalent in the US.

A mid-season analysis of the influenza vaccine by the US Department of Defensive (DoD) Global Respiratory Pathogen Surveillance Program (DoDGRPSP) has reported low to moderate vaccine effectiveness (VE). 

The study included 295 Military Health System (MHS) beneficiaries (adults and children) who tested positive for influenza and 965 controls who tested negative. Vaccinated patients had received the 2024-2025 influenza vaccine at least 14 days prior to symptom onset. The study conducted VE analyses for influenza A (any subtype), influenza A(H1N1)pdm09, and influenza A(H3N2). 

Overall, moderate effectiveness against influenza A(H1N1)pdm09 was reported in all beneficiaries and children aged 6 months to 17 years. In adults aged 18 to 64 years—and all beneficiaries—there was moderate effectiveness against influenza A(H3N2). VE estimates against influenza A (any subtype) for all beneficiaries, children, and adults were not significant; VE estimates were also not effective among children for influenza A(H3N2) and in adults for influenza A(H1N1)pdm09.

Adjusted VE estimates among all participants for influenza A (any subtypes), influenza A(H1N1)pdm09, and influenza A(H3N2) were 25%, 58%, and 42%, respectively. VE for influenza B was not calculated due to a low number of cases.

Flu vaccination rates for adults are usually in the 30% to 60% range despite the recommended target of 70%. Flu vaccination rates were rising by around 1% to 2% annually before 2020, but began dropping after the COVID-19 pandemic, especially in higher-risk groups. In adults aged ≥ 65 years, flu vaccination rates dropped from 52% in 2019-2020 to 43% in 2024-2025.

According to the Centers for Disease Control and Prevention (CDC), at the end of the 2023-2024 flu season, 9.2 million fewer doses were administered in pharmacies and doctors offices compared with the baseline before the COVID-19 pandemic. Since 2022, private manufacturers have distributed significantly fewer influenza vaccine doses. 

Each March, the US Food and Drug Association (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) meets to analyze the current influenza season and forecast the next. The committee reviews and discusses data on influenza strain circulation and VE, which come from DoDGRPSP analyses. In February, US Department of Health and Human Services officials indefinitely postponed a public meeting of the CDC Advisory Committee on Immunization Practice (ACIP), at which members were also expected to discuss, among other things, VE and vaccine recommendations. The FDA canceled a March 13 VRBPAC meeting and provided no reason for the cancelation to members. That day, however, the FDA issued new recommendations for the influenza vaccine for the 2025-2026 season without the input of VRBPAC. Instead, experts from the FDA, CDC, and DoD made recommendations after reviewing surveillance data from the US and globally.

For the 2025-2026 influenza season, the FDA recommends the vaccines be trivalent and target 2 strains of influenza A and 1 strain of influenza B. The FDA anticipates there will be an “adequate and diverse supply” of approved trivalent seasonal influenza vaccines. Trivalent flu vaccines are formulated to protect against 3 influenza viruses: an A(H1N1) virus, an A(H3N2) virus, and a B/Victoria virus. All influenza vaccines for the 2025-2026 season are anticipated to be trivalent in the US.

A mid-season analysis of the influenza vaccine by the US Department of Defensive (DoD) Global Respiratory Pathogen Surveillance Program (DoDGRPSP) has reported low to moderate vaccine effectiveness (VE). 

The study included 295 Military Health System (MHS) beneficiaries (adults and children) who tested positive for influenza and 965 controls who tested negative. Vaccinated patients had received the 2024-2025 influenza vaccine at least 14 days prior to symptom onset. The study conducted VE analyses for influenza A (any subtype), influenza A(H1N1)pdm09, and influenza A(H3N2). 

Overall, moderate effectiveness against influenza A(H1N1)pdm09 was reported in all beneficiaries and children aged 6 months to 17 years. In adults aged 18 to 64 years—and all beneficiaries—there was moderate effectiveness against influenza A(H3N2). VE estimates against influenza A (any subtype) for all beneficiaries, children, and adults were not significant; VE estimates were also not effective among children for influenza A(H3N2) and in adults for influenza A(H1N1)pdm09.

Adjusted VE estimates among all participants for influenza A (any subtypes), influenza A(H1N1)pdm09, and influenza A(H3N2) were 25%, 58%, and 42%, respectively. VE for influenza B was not calculated due to a low number of cases.

Flu vaccination rates for adults are usually in the 30% to 60% range despite the recommended target of 70%. Flu vaccination rates were rising by around 1% to 2% annually before 2020, but began dropping after the COVID-19 pandemic, especially in higher-risk groups. In adults aged ≥ 65 years, flu vaccination rates dropped from 52% in 2019-2020 to 43% in 2024-2025.

According to the Centers for Disease Control and Prevention (CDC), at the end of the 2023-2024 flu season, 9.2 million fewer doses were administered in pharmacies and doctors offices compared with the baseline before the COVID-19 pandemic. Since 2022, private manufacturers have distributed significantly fewer influenza vaccine doses. 

Each March, the US Food and Drug Association (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) meets to analyze the current influenza season and forecast the next. The committee reviews and discusses data on influenza strain circulation and VE, which come from DoDGRPSP analyses. In February, US Department of Health and Human Services officials indefinitely postponed a public meeting of the CDC Advisory Committee on Immunization Practice (ACIP), at which members were also expected to discuss, among other things, VE and vaccine recommendations. The FDA canceled a March 13 VRBPAC meeting and provided no reason for the cancelation to members. That day, however, the FDA issued new recommendations for the influenza vaccine for the 2025-2026 season without the input of VRBPAC. Instead, experts from the FDA, CDC, and DoD made recommendations after reviewing surveillance data from the US and globally.

For the 2025-2026 influenza season, the FDA recommends the vaccines be trivalent and target 2 strains of influenza A and 1 strain of influenza B. The FDA anticipates there will be an “adequate and diverse supply” of approved trivalent seasonal influenza vaccines. Trivalent flu vaccines are formulated to protect against 3 influenza viruses: an A(H1N1) virus, an A(H3N2) virus, and a B/Victoria virus. All influenza vaccines for the 2025-2026 season are anticipated to be trivalent in the US.

The SARS-CoV-2 virus has resulted in > 778 million reported COVID-19 cases and > 7 million deaths worldwide. ¹ About 70% of the eligible US population has completed a primary COVID-19 vaccination series, yet only 17% have received an updated bivalent booster dose.² These immunization rates fall below the World Health Organization (WHO) target of 70%.³

Early in the pandemic, US Department of Veterans Affairs (VA) vaccination rates ranged from 46% to 71%.^4,5 Ensuring a high level of COVID-19 vaccination in the largest integrated US health care system aligns with the VA priority to provide high-quality, evidence-based care to a patient population that is older and has more comorbidities than the overall US population.^6-9

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite availability of vaccination service,” is a major contributor to suboptimal vaccination rates.^10-13 Previous studies used cluster analyses to identify the unique combinations of behavioral and social factors responsible for COVID-19 vaccine hesitancy.^10,11 Lack of perceived vaccine effectiveness and low perceived risk of the health consequences from COVID-19 infection were frequently identified in clusters where patients had the lowest intent for vaccination.^10,11 Similarly, low trust in health care practitioners (HCPs), government, and pharmaceutical companies diminished intent for vaccination in these clusters.¹⁰ These quantitative studies were limited by their exclusive focus on unvaccinated individuals, reliance on self-reported intent, and lack of assessment of a health care system with a COVID-19 vaccine delivery program designed to overcome barriers to health care access, such as the VA.

Prior qualitative studies of vaccine uptake in distinct veteran subgroups (ie, unhoused and in VA facilities with low vaccination rates) demonstrated that overriding medical priorities among the unhoused and vaccine safety concerns were associated with decreased vaccine uptake, and positive perceptions of HCPs and the health care system were associated with increased vaccine uptake.^11,12 However, these studies were conducted during periods of greater COVID-19 vaccine availability and acceptance, and prior to booster recommendations.^4,12,13

This mixed-methods quality improvement (QI) project assessed the barriers and facilitators of COVID-19 vaccination among veterans receiving primary care at a single VA health care facility. We assessed whether unique patient clusters could be identified based on COVID-19–related and vaccine-related thoughts and feelings and whether cluster membership was associated with COVID-19 vaccination. This analysis also explored how individuals’ beliefs and trust shaped motivations and hesitancies for vaccine uptake in quantitatively derived clusters with varying vaccination rates.

Methods

This QI project was conducted at the VA Pittsburgh Healthcare System (VAPHS), a tertiary care facility serving > 75,000 veterans in Pennsylvania, West Virginia, and Ohio. The VAPHS Institutional Review Board determined this QI study was exempt from review.^14-17 Participation was voluntary and had no bearing on VA health care or benefits. Financial support for the project, including key personnel and participant compensation, was provided by VAPHS. We followed the STROBE reporting guideline for cross-sectional studies and the COREQ checklist for qualitative research.^18,19

Quantitative Survey

The 32,271 veterans assigned to a VAPHS primary care HCP, effective April 1, 2020, were eligible. To ensure representation of subgroups underrecognized in research and/or QI projects, the sample included all 1980 female patients at VAPHS and a random sample of 500 White and 500 Hispanic and/or non-White men within 4 age categories (< 50, 50-64, 65-84, and > 84 years). For the < 50 years or > 84 years categories, all Hispanic and/or non-White men were included due to small sample sizes.^20-22 The nonrandom sampling frame comprised 1708 Hispanic and/or non-White men and 2000 White men. After assigning the 5688 potentially eligible individuals a unique identifier, 31 opted out, resulting in a final sample of 5657 individuals.

The 5657 individuals received a letter requesting their completion of a future questionnaire about COVID-19 infection and vaccines. An electronic Qualtrics questionnaire link was emailed to 3221 individuals; nonresponders received 2 follow-up email reminders. For the 2436 veterans without an email address on file, trained interviewers conducted phone surveys and entered responses. Those patients who completed the questionnaire could enter a drawing to win 1 of 100 cash prizes valued at $100. We collected questionnaire data from July to September 2021.

Questionnaire Items

We constructed a 60-item questionnaire based on prior research on COVID-19 vaccine hesitancy and the WHO Guidebook for Immunization Programs and Implementing Partners.^4,23-25 The WHO Guidebook comprises survey items organized within 4 domains reflecting the behavioral and social determinants of vaccination: thoughts and feelings; social processes; motivation and hesitancy; and practical factors.²³

Sociodemographic, clinical, and personal characteristics. The survey assessed respondent ethnicity and race and used these data to create a composite race and ethnicity variable. Highest educational level was also attained using 8 response options. The survey also assessed prior COVID-19 infection; prior receipt of vaccines for influenza, pneumonia, tetanus, or shingles; and presence of comorbidities that increase the risk of severe COVID-19 infection. We used administrative data from the VA Corporate Data Warehouse to determine respondent age, sex, geographic residence (urban, rural), and to fill in missing self-reported data on sex (n = 4) and ethnicity and race (n = 12). The survey assessed political views using a 5-point Likert scale (1, very liberal; 5, very conservative) and was collapsed into 3 categories (ie, very conservative or conservative, moderate, very liberal or liberal), with prefer not to answer reported separately

COVID-19 infection and vaccine. We asked veterans if they had ever been infected with COVID-19, whether they had been offered and/or received a COVID-19 vaccine, and type (Pfizer, Moderna, or Johnson & Johnson), and number of doses received. Positive vaccination status was defined as the receipt of ≥ 1 dose of a COVID-19 vaccine approved by the US Food and Drug Administration.

COVID-19 opinions. Respondents were asked about perceived risk of COVID-19 infection and related health outcomes, as well as beliefs about COVID-19 vaccines, using a 4-point Likert scale for all items: (1, not at all concerned; 4, very concerned). Respondents were asked about concerns related to COVID-19 infection and severe illness. They also were asked about vaccine-related short-term adverse effects (AEs) and long-term complications. Respondents were asked how effective they believed COVID-19 vaccines were at preventing infection, serious illness, or death. Unvaccinated and vaccinated veterans were asked similar items, with a qualifier of “before getting vaccinated…” for those who were vaccinated.

Social processes. Respondents were asked to rate their level of trust in various sources of COVID-19 vaccine information using a 4-point Likert scale (1, trust not at all; 4, trust very much). Respondents were asked whether community or religious leaders or close family or friends wanted them to get vaccinated (yes, no, or unsure).

Practical factors. Respondents were asked to rate the logistical difficulty of getting vaccinated or trying to get vaccinated using a 4-point Likert scale (1, not at all; 4, extremely).

Participants

Respondents were asked to participate in a follow-up qualitative interview. Among 293 participants who agreed, we sampled all 86 unvaccinated individuals regardless of cluster assignment, a random sample of 88 individuals in the cluster with the lowest vaccination rate, and all 33 vaccinated individuals in the cluster with the second-lowest vaccination rate. Forty-nine veterans completed qualitative interviews.

Two research staff trained in qualitative research completed telephone interviews, averaging 16.5 minutes (March to May 2022), using semistructured scripts to elicit vaccine-related motivations, hesitancies, or concerns. Interviews were recorded, transcribed, and deidentified. Participants provided written consent for recording and received $50 cash-equivalent compensation for interview completion.

Qualitative Interview Script

The interview script consisted of open-ended questions related to vaccine uptake across WHO domains.²³ Both unvaccinated and vaccinated respondents were asked similar questions and customized questions about boosters for the vaccinated subgroup. To assess motivations and hesitancies, respondents were asked how they made their decisions about vaccination and what they considered when deciding. Vaccinated participants were asked about motivations and overcoming concerns. Unvaccinated respondents were asked about reasons for concern. To assess social processes, the interviewers asked participants whose opinion or counsel they trusted when deciding whether to get vaccinated. Questions also focused on positive experiences and vaccination barriers. Vaccinated participants were asked what could have improved their vaccination experiences. Finally, the interviewers asked participants who received a complete primary vaccine series about their motivations and plans related to booster vaccines, and whether information about emerging COVID-19 variants influenced their decisions.

Data Analyses

This analysis used X² and Fisher exact tests to assess the associations among respondent characteristics, questionnaire responses, vaccination status, and cluster membership. Items phrased similarly were handled in a similar fashion for vaccinated and unvaccinated respondents.

Cluster analysis assessed the possible groupings in responses to the quantitative questionnaire items focused on thoughts and feelings about COVID-19 infection risk and severity, vaccine effectiveness, and vaccine safety. This analysis treated the items’ ordinal response categories as continuous. We performed factor analysis using principal component analysis to explore dimension reduction and account for covariance between items. Two principal components were calculated and applied k-means clustering, determining the number of clusters through agreement from the elbow, gap statistic, and silhouette methods.²⁶ Each cluster was named based on its unique pattern of responses to the items used to define them (eAppendix 1).

Multivariable logistic regression analyses assessed the independent association between cluster membership as the independent measure and vaccination status as the dependent measure, adjusting for respondent sociodemographic and personal characteristics and 2 measures of trust (ie, local VA HCP and the CDC). We selected these trust measures because they represent objective sources of medical information and were independently associated with COVID-19 vaccination status in a logistic regression model comprising all 6 trust items assessed.

This study defined statistical significance as a 2-tailed P value < .05. SAS 9.4 was used for all statistical analyses and Python 3.7.4 and the Scikit-learn package for cluster analyses.²⁷ For qualitative analyses, this study used an inductive thematic approach guided by conventional qualitative content analysis, NVivo 12 Plus for Windows to code and analyze interview transcripts.^28,29 We created an initial codebook based on 10 transcripts that were selected for high complexity and represented cluster membership and vaccination status.^30,31 After 2 qualitative staff developed the initial codebook, 11 of 49 (22%) transcripts were independently coded by a primary and secondary coder to ensure consistent code application. Both coders reviewed the cocoded transcripts and resolved all discrepancies through negotiated consensus.³² After the cocoding process was complete, the primary coder coded the remaining transcripts. The primary and secondary coder met as needed to review and discuss any questions that arose during the primary coder’s work.

Results

Of 5657 eligible participants, 1208 (21.4%) completed a questionnaire. Overall, 674 (55.8%) were aged < 65 years, 530 (43.9%) were women, 828 (68.5%) were non-Hispanic White, 303 (25.1%) were Black, and 47 (3.9%) were Hispanic, and 1034 (85.6%) were vaccinated (Table 1). Compared to the total sampled population, respondents were more often older, female, and White (eAppendix 2).

Cluster Membership

Four clusters were identified from 1183 (97.9%) participants who provided complete responses to 6 items assessing thoughts and feelings about COVID-19 infection and vaccines (Table 2). Of the 1183 respondents, 375 (31.7%) were Concerned Believers (cluster 1), 336 (28.4%) were Unconcerned Believers (cluster 2), 298 (25.2%) were Concerned Ambivalents (cluster 3), and 174 (14.7%) were Unconcerned Disbelievers (cluster 4). The Concerned Believers were moderately/ very concerned about COVID-19 infection (96.0%) and becoming very ill from infection (94.6%), believed the vaccine was moderately/very effective in preventing COVID-19 infection (100%) and severe illness or death from infection (98.7%), and had slight concern about short-term AEs (92.6%) or long-term complications (92.0%) from the vaccine. The Unconcerned Believers had no/slight concern about COVID-19 infection (76.5%) or becoming very ill (79.2%), believed the vaccine was effective in preventing infection (82.4%) and severe illness and death (83.6%), and had no/slight concern about short-term AEs (94.0%) or long-term complications (87.2%) from the vaccine. The Concerned Ambivalents were moderately/ very concerned about COVID-19 infection (94.3%) and becoming very ill (93.6%), believed the vaccine was moderately/very effective in preventing infection (86.6%) and severe illness or death (86.9%), and were moderately/very concerned about short-term AEs (81.9%) or long-term complications (89.3%) from the vaccine. The Unconcerned Disbelievers had no/slight concern about COVID-19 infection (90.8%) and becoming very ill (88.6%), believed the vaccine was not at all/slightly effective in preventing infection (90.3%) and severe illness or death (87.4%), and were moderately/very concerned about short-term AEs (52.8%) or long-term complications (75.9%) from the vaccine.

Cluster Membership

Respondent age, race and ethnicity, and political viewpoints differed significantly by cluster (P < .001). Compared with the other clusters, the Concerned Believer cluster was older (55.5% age ≥ 65 years vs 16.7%-48.0%) and more frequently reported liberal political views (28.8% vs 4.6%-15.1%). In contrast, the Unconcerned Disbeliever cluster was younger (83.4% age ≤ 64 years vs 44.5%-56.8%) and more frequently reported conservative political views (37.9% vs 17.1%-26.8%) than the other clusters. Whereas the Concerned Ambivalent cluster had the highest proportion of Black (37.7%) and the lowest proportion of White respondents (57.6%), the Unconcerned Disbelievers cluster had the lowest proportion of Black respondents (14.5%) and the highest proportion of White respondents (77.9%). The Unconcerned Disbelievers cluster were significantly less likely to trust COVID-19 vaccine information from any source and to believe those close to them wanted them to get vaccinated.

Association of Cluster Membership and COVID-19 Vaccination

COVID-19 vaccination rates varied more than 3-fold (P < .001) by cluster, with 29.9% of Unconcerned Disbelievers, 93.3% of Concerned Ambivalents, 93.5% of Unconcerned Believers, and 98.9% of Concerned Believers reporting being vaccinated. (Figure). Cluster membership was independently associated with vaccination, with adjusted odds ratios (AORs) of 12.0 (95% CI, 6.1-23.8) for the Concerned Ambivalent, 13.0 (95% CI, 6.9-24.5) for Unconcerned Believer, and 48.6 (95% CI, 15.5-152.1) for Concerned Believer clusters (Table 3). Respondent trust in COVID-19 vaccine information from their VA HCP (AOR 2.1; 95% CI, 1.6-2.8) and the CDC (AOR 1.6; 95% CI, 1.2-2.1) were independently associated with vaccination status, while the remaining respondent sociodemographic or personal characteristics were not.

Qualitative Interview Participants

A 49-participant convenience sample completed interviews, including 30 Concerned Ambivalent, 17 Unconcerned Disbeliever, and 2 Unconcerned Believer respondents cluster. The data were not calculated for Unconcerned Believers due to the small sample size. Interview participants were more likely to be younger, female, non-Hispanic, White, less educated, and more politically conservative than the questionnaire respondents as a whole (Appendix). The vaccination rate for the interview participants was 73.5%, ranging from 29.9% in the Unconcerned Disbeliever to 93.3% in the Concerned Ambivalent cluster. Qualitative themes and participant quotes for Concerned Ambivalent and Unconcerned Disbeliever respondents are in eAppendix 3.

Motivations. Wanting personal protection from becoming infected or severely ill from COVID-19 (63.8%), caregiver wanting to protect others (17.0%), and employment vaccine requirements (14.9%) were frequent motivations for vaccination. Whereas personal protection (90.0%) and protection of others (23.3%) were identified more frequently in the Concerned Ambivalents cluster, employment vaccine requirements (35.3%) were more frequently identified in the Unconcerned Disbelievers cluster.

Hesitancies or concerns. Lack of sufficient information related to rapid vaccine development (55.3%), vaccine AEs (38.3%), and low confidence in vaccine efficacy (23.4%) were frequent concerns or hesitancies about vaccination. Unconcerned Disbelievers expressed higher levels of concern about the vaccine’s rapid development (82.4%), low perceived vaccine efficacy (47.1%), and a lack of trust in governmental vaccine promotion (23.5%) than did the Concerned Ambivalents.

Overcoming concerns. Not wanting to get sick or die from infection coupled with an understanding that vaccine benefits exceed risks (23.4%) and receiving information from a trusted source (10.6%) were common ways of overcoming concerns for vaccination. Although the Unconcerned Disbelievers infrequently identified reasons for overcoming concerns, they identified employment requirements (17.6%) as a reason for vaccination despite concerns. They also identified seeing others with positive vaccine experiences and pressure from family or friends as ways of overcoming concerns (11.8% each).

Social influences. Family members or partners (38.3%), personal opinions (38.3%), and HCPs (23.4%) were frequent social influences for vaccination. Concerned Ambivalents mentioned family members and partners (46.7%), HCPs (26.7%), and friends (20.0%) as common influences, while Unconcerned Disbelievers more frequently relied on their opinion (41.2%) and quoted specific scientifically reputable data sources (17.6%) to guide vaccine decision-making, although it is unclear whether these sources were accessed directly or if this information was obtained indirectly through scientifically unvetted data platforms.

Practical factors. Most participants had positive vaccination experiences (68.1%), determined mainly by the Concerned Ambivalents (90.0%), who were more highly vaccinated. Barriers to vaccination were reported by 9 (19.1%) participants, driven by those in the Concerned Ambivalent cluster (26.7%). Eight (17.0%) participants suggested improvements for vaccination processes, with similar overall reporting frequencies across clusters.

COVID-19 boosters and variants. Wanting continued protection from COVID-19 (36.2%), recommendations from a doctor or trusted source (17.0%), and news about emerging variants (10.6%) were frequent motivations for receiving a vaccine booster (eAppendix 4). These motivations were largely driven by the Concerned Ambivalents, of whom 25 of 30 were booster eligible and 24 received a booster dose. Belief that boosters were unnecessary (8.5%), concerns about efficacy (6.4%), and concerns about AEs (6.4%) were frequently identified hesitancies. These concerns were expressed largely by the Unconcerned Disbelievers, of whom 7 of 17 were booster dose eligible, but only 1 received a dose.

Evolving knowledge about variants was not a major concern overall and did not change existing opinions about the vaccine (36.2%). Concerned Ambivalents believed vaccination provided extra protection against variants (36.7%) and the emergence of variants served as a reminder of the ongoing pandemic (30.0%). In contrast, Unconcerned Disbelievers believed that the threat of variants was overblown (35.3%) and mutations are to be expected (17.6%).

Discussion

This study used a complementary mixed-methods approach to understand the motivations, hesitancies, and social and practical drivers of COVID-19 vaccine uptake among VA beneficiaries. Our quantitative analyses identified 4 distinct clusters based on respondents’ opinions on COVID-19 infection severity and vaccine effectiveness and safety. Veterans in 3 clusters were 12 to 49 times more likely to be vaccinated than those in the remaining cluster, even when controlling for baseline respondent characteristics and level of trust in credible sources of COVID-19 information. The observed vaccination rate of nearly 86% was higher than the contemporaneous national average of 62% for vaccine-eligible individuals, likely reflecting the comprehensive VA vaccine promotion strategies tailored to a patient demographic with a high COVID-19 risk profile.^2,10

This cluster analyses demonstrated the importance of thoughts and feelings about COVID-19 infection and vaccination as influential social and behavioral drivers of vaccine uptake. These opinions help explain the strong association between cluster membership and vaccination status in this multivariable modeling. The cluster composition was consistent with findings from studies of nonveteran populations that identified perceived vulnerability to COVID-19 infection, beliefs in vaccine effectiveness, and adherence with protective behaviors during the pandemic as contributors to vaccine uptake.^13,33 Qualitative themes showed that personal protection, protecting others, and vaccine mandates were frequent motivators for vaccination. Whereas protection of self and others from COVID-19 infection were more often expressed by the highly vaccinated Concerned Ambivalents, employment and travel vaccine mandates were more often identified by Unconcerned Disbelievers, who had a lower vaccination rate. Among Unconcerned Disbelievers, an employer vaccine requirement was the most frequent qualitative theme for overcoming vaccination concerns.

In addition to cluster membership, our modeling showed that trust in local VA HCPs and the CDC were independently associated with COVID-19 vaccination, which has been found in prior research.²⁰ This qualitative analyses regarding vaccine hesitancy identified trust-related concerns that were more frequently expressed by Unconcerned Disbelievers than Concerned Ambivalents. Concerns included the rapid development of the vaccines potentially limiting the generation of scientifically sound effectiveness and safety data, and potential biases involving the entities promoting vaccine uptake.

Whereas the Concerned Believers, Unconcerned Believers, and Concerned Ambivalents all had high COVID-19 vaccination rates (≥ 93%), the decision-making pathways to vaccine uptake likely differ by their concerns about COVID-19 infection and perceptions of vaccine safety and effectiveness. For example, this mixed-methods analysis consistently showed that people in the Concerned Ambivalent cluster were positively motivated by concerns about COVID-19 infection and severity and beliefs about vaccine effectiveness that were tempered by concerns about vaccine AEs. For this cluster, their frequent thematic expression that the benefits of the vaccine exceed the risks, and the positive social influences of family, friends, and HCPs may explain their high vaccination rate.

Such insights into how the patterns of COVID-19–related thoughts and feelings vary across clusters can be used to design interventions to encourage initial and booster doses of COVID-19 vaccines. For example, messaging that highlights the infectivity and severity of COVID-19 and the potential for persistent negative health outcomes associated with long COVID could reinforce the beliefs of Concerned Believers and Concerned Ambivalents, and such messaging could also be used as a targeted intervention for Unconcerned Believers who expressed fewer concerns about the health consequences of COVID-19.23 Likewise, messaging about the safety profile of COVID-19 vaccines may reduce vaccine hesitancy for Concerned Ambivalents. Importantly, purposeful attention to health equity, community engagement, and involvement of racially diverse HCPs in patient discussions represent successful strategies to increase COVID-19 vaccine uptake among Black individuals, who were disproportionately represented in the Concerned Ambivalent cluster and may possess higher levels of mistrust due to racism experienced within the health care system.²⁴

Our findings suggest that the greatest challenge for overcoming vaccine hesitancy is for individuals in the suboptimally vaccinated (30%) Unconcerned Disbeliever cluster. These individuals had low levels of concern about COVID-19 infection and severity, high levels of concern about vaccine safety, low perceived vaccine effectiveness, and low levels of trust in all information sources about COVID-19. While the Unconcerned Disbelievers cited scientifically reputable data sources, we were unable to verify whether participants accessed these reputable sources of information directly or obtained such information indirectly through potentially biased online sources. Nearly half of this cluster trusted their VA HCP and believed their community or religious leaders would want them to get vaccinated. This qualitative analyses found that Unconcerned Disbelievers relied on personal beliefs for vaccine decision-making more than Concerned Ambivalents. While Unconcerned Disbelievers were less likely to be socially influenced by family, friends, or religious leaders, they still acknowledged some impact from these sources. These findings suggest that addressing vaccine hesitancy among Unconcerned Disbelievers may require a multifaceted approach that respects their reliance on personal research while also leveraging the potential social influences. This approach supports the promising, previously reported practices of harnessing the social influences of HCPs and other community and religious leaders to promote vaccine uptake among Unconcerned Disbelievers.^34,35 One evidence-based approach to effectively change patient health care behaviors is through motivational interviewing strategies that use open-ended questions, nonjudgmental interactions, and collaborative decision-making when discussing the risks and benefits of vaccination.^21,22

Limitations

This study was conducted at a single VA health care facility and our sampling technique was nonrandom, suggesting that these results may not be generalizable to all veterans or non-VA patient populations. The 21% questionnaire response rate could have introduced selection bias into the respondent sample. All questionnaire data were self-reported, including vaccination status. Finally, the qualitative interviews consisted of a small number of unvaccinated individuals in 2 clusters (ie, Concerned Ambivalents and Unconcerned Disbelievers) and may not have reached thematic saturation in these subgroups.

Conclusions

Quantitative analyses identified 4 clusters based on individual thoughts and feelings about COVID-19 infection and vaccines. Cluster membership and levels of trust in COVID-19 information sources were independently associated with vaccination. Understanding the quantitative patterns of thoughts and beliefs across clusters, enriched by common qualitative themes for vaccine hesitancy, help inform tailored interventions to augment COVID-19 vaccine uptake and highlight the importance of targeted, trust-based communication and culturally sensitive interventions to enhance vaccine uptake across diverse populations.

The SARS-CoV-2 virus has resulted in > 778 million reported COVID-19 cases and > 7 million deaths worldwide. ¹ About 70% of the eligible US population has completed a primary COVID-19 vaccination series, yet only 17% have received an updated bivalent booster dose.² These immunization rates fall below the World Health Organization (WHO) target of 70%.³

Early in the pandemic, US Department of Veterans Affairs (VA) vaccination rates ranged from 46% to 71%.^4,5 Ensuring a high level of COVID-19 vaccination in the largest integrated US health care system aligns with the VA priority to provide high-quality, evidence-based care to a patient population that is older and has more comorbidities than the overall US population.^6-9

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite availability of vaccination service,” is a major contributor to suboptimal vaccination rates.^10-13 Previous studies used cluster analyses to identify the unique combinations of behavioral and social factors responsible for COVID-19 vaccine hesitancy.^10,11 Lack of perceived vaccine effectiveness and low perceived risk of the health consequences from COVID-19 infection were frequently identified in clusters where patients had the lowest intent for vaccination.^10,11 Similarly, low trust in health care practitioners (HCPs), government, and pharmaceutical companies diminished intent for vaccination in these clusters.¹⁰ These quantitative studies were limited by their exclusive focus on unvaccinated individuals, reliance on self-reported intent, and lack of assessment of a health care system with a COVID-19 vaccine delivery program designed to overcome barriers to health care access, such as the VA.

Prior qualitative studies of vaccine uptake in distinct veteran subgroups (ie, unhoused and in VA facilities with low vaccination rates) demonstrated that overriding medical priorities among the unhoused and vaccine safety concerns were associated with decreased vaccine uptake, and positive perceptions of HCPs and the health care system were associated with increased vaccine uptake.^11,12 However, these studies were conducted during periods of greater COVID-19 vaccine availability and acceptance, and prior to booster recommendations.^4,12,13

This mixed-methods quality improvement (QI) project assessed the barriers and facilitators of COVID-19 vaccination among veterans receiving primary care at a single VA health care facility. We assessed whether unique patient clusters could be identified based on COVID-19–related and vaccine-related thoughts and feelings and whether cluster membership was associated with COVID-19 vaccination. This analysis also explored how individuals’ beliefs and trust shaped motivations and hesitancies for vaccine uptake in quantitatively derived clusters with varying vaccination rates.

Methods

This QI project was conducted at the VA Pittsburgh Healthcare System (VAPHS), a tertiary care facility serving > 75,000 veterans in Pennsylvania, West Virginia, and Ohio. The VAPHS Institutional Review Board determined this QI study was exempt from review.^14-17 Participation was voluntary and had no bearing on VA health care or benefits. Financial support for the project, including key personnel and participant compensation, was provided by VAPHS. We followed the STROBE reporting guideline for cross-sectional studies and the COREQ checklist for qualitative research.^18,19

Quantitative Survey

The 32,271 veterans assigned to a VAPHS primary care HCP, effective April 1, 2020, were eligible. To ensure representation of subgroups underrecognized in research and/or QI projects, the sample included all 1980 female patients at VAPHS and a random sample of 500 White and 500 Hispanic and/or non-White men within 4 age categories (< 50, 50-64, 65-84, and > 84 years). For the < 50 years or > 84 years categories, all Hispanic and/or non-White men were included due to small sample sizes.^20-22 The nonrandom sampling frame comprised 1708 Hispanic and/or non-White men and 2000 White men. After assigning the 5688 potentially eligible individuals a unique identifier, 31 opted out, resulting in a final sample of 5657 individuals.

The 5657 individuals received a letter requesting their completion of a future questionnaire about COVID-19 infection and vaccines. An electronic Qualtrics questionnaire link was emailed to 3221 individuals; nonresponders received 2 follow-up email reminders. For the 2436 veterans without an email address on file, trained interviewers conducted phone surveys and entered responses. Those patients who completed the questionnaire could enter a drawing to win 1 of 100 cash prizes valued at $100. We collected questionnaire data from July to September 2021.

Questionnaire Items

We constructed a 60-item questionnaire based on prior research on COVID-19 vaccine hesitancy and the WHO Guidebook for Immunization Programs and Implementing Partners.^4,23-25 The WHO Guidebook comprises survey items organized within 4 domains reflecting the behavioral and social determinants of vaccination: thoughts and feelings; social processes; motivation and hesitancy; and practical factors.²³

Sociodemographic, clinical, and personal characteristics. The survey assessed respondent ethnicity and race and used these data to create a composite race and ethnicity variable. Highest educational level was also attained using 8 response options. The survey also assessed prior COVID-19 infection; prior receipt of vaccines for influenza, pneumonia, tetanus, or shingles; and presence of comorbidities that increase the risk of severe COVID-19 infection. We used administrative data from the VA Corporate Data Warehouse to determine respondent age, sex, geographic residence (urban, rural), and to fill in missing self-reported data on sex (n = 4) and ethnicity and race (n = 12). The survey assessed political views using a 5-point Likert scale (1, very liberal; 5, very conservative) and was collapsed into 3 categories (ie, very conservative or conservative, moderate, very liberal or liberal), with prefer not to answer reported separately

COVID-19 infection and vaccine. We asked veterans if they had ever been infected with COVID-19, whether they had been offered and/or received a COVID-19 vaccine, and type (Pfizer, Moderna, or Johnson & Johnson), and number of doses received. Positive vaccination status was defined as the receipt of ≥ 1 dose of a COVID-19 vaccine approved by the US Food and Drug Administration.

COVID-19 opinions. Respondents were asked about perceived risk of COVID-19 infection and related health outcomes, as well as beliefs about COVID-19 vaccines, using a 4-point Likert scale for all items: (1, not at all concerned; 4, very concerned). Respondents were asked about concerns related to COVID-19 infection and severe illness. They also were asked about vaccine-related short-term adverse effects (AEs) and long-term complications. Respondents were asked how effective they believed COVID-19 vaccines were at preventing infection, serious illness, or death. Unvaccinated and vaccinated veterans were asked similar items, with a qualifier of “before getting vaccinated…” for those who were vaccinated.

Social processes. Respondents were asked to rate their level of trust in various sources of COVID-19 vaccine information using a 4-point Likert scale (1, trust not at all; 4, trust very much). Respondents were asked whether community or religious leaders or close family or friends wanted them to get vaccinated (yes, no, or unsure).

Practical factors. Respondents were asked to rate the logistical difficulty of getting vaccinated or trying to get vaccinated using a 4-point Likert scale (1, not at all; 4, extremely).

Participants

Respondents were asked to participate in a follow-up qualitative interview. Among 293 participants who agreed, we sampled all 86 unvaccinated individuals regardless of cluster assignment, a random sample of 88 individuals in the cluster with the lowest vaccination rate, and all 33 vaccinated individuals in the cluster with the second-lowest vaccination rate. Forty-nine veterans completed qualitative interviews.

Two research staff trained in qualitative research completed telephone interviews, averaging 16.5 minutes (March to May 2022), using semistructured scripts to elicit vaccine-related motivations, hesitancies, or concerns. Interviews were recorded, transcribed, and deidentified. Participants provided written consent for recording and received $50 cash-equivalent compensation for interview completion.

Qualitative Interview Script

The interview script consisted of open-ended questions related to vaccine uptake across WHO domains.²³ Both unvaccinated and vaccinated respondents were asked similar questions and customized questions about boosters for the vaccinated subgroup. To assess motivations and hesitancies, respondents were asked how they made their decisions about vaccination and what they considered when deciding. Vaccinated participants were asked about motivations and overcoming concerns. Unvaccinated respondents were asked about reasons for concern. To assess social processes, the interviewers asked participants whose opinion or counsel they trusted when deciding whether to get vaccinated. Questions also focused on positive experiences and vaccination barriers. Vaccinated participants were asked what could have improved their vaccination experiences. Finally, the interviewers asked participants who received a complete primary vaccine series about their motivations and plans related to booster vaccines, and whether information about emerging COVID-19 variants influenced their decisions.

Data Analyses

This analysis used X² and Fisher exact tests to assess the associations among respondent characteristics, questionnaire responses, vaccination status, and cluster membership. Items phrased similarly were handled in a similar fashion for vaccinated and unvaccinated respondents.

Cluster analysis assessed the possible groupings in responses to the quantitative questionnaire items focused on thoughts and feelings about COVID-19 infection risk and severity, vaccine effectiveness, and vaccine safety. This analysis treated the items’ ordinal response categories as continuous. We performed factor analysis using principal component analysis to explore dimension reduction and account for covariance between items. Two principal components were calculated and applied k-means clustering, determining the number of clusters through agreement from the elbow, gap statistic, and silhouette methods.²⁶ Each cluster was named based on its unique pattern of responses to the items used to define them (eAppendix 1).

Multivariable logistic regression analyses assessed the independent association between cluster membership as the independent measure and vaccination status as the dependent measure, adjusting for respondent sociodemographic and personal characteristics and 2 measures of trust (ie, local VA HCP and the CDC). We selected these trust measures because they represent objective sources of medical information and were independently associated with COVID-19 vaccination status in a logistic regression model comprising all 6 trust items assessed.

This study defined statistical significance as a 2-tailed P value < .05. SAS 9.4 was used for all statistical analyses and Python 3.7.4 and the Scikit-learn package for cluster analyses.²⁷ For qualitative analyses, this study used an inductive thematic approach guided by conventional qualitative content analysis, NVivo 12 Plus for Windows to code and analyze interview transcripts.^28,29 We created an initial codebook based on 10 transcripts that were selected for high complexity and represented cluster membership and vaccination status.^30,31 After 2 qualitative staff developed the initial codebook, 11 of 49 (22%) transcripts were independently coded by a primary and secondary coder to ensure consistent code application. Both coders reviewed the cocoded transcripts and resolved all discrepancies through negotiated consensus.³² After the cocoding process was complete, the primary coder coded the remaining transcripts. The primary and secondary coder met as needed to review and discuss any questions that arose during the primary coder’s work.

Results

Of 5657 eligible participants, 1208 (21.4%) completed a questionnaire. Overall, 674 (55.8%) were aged < 65 years, 530 (43.9%) were women, 828 (68.5%) were non-Hispanic White, 303 (25.1%) were Black, and 47 (3.9%) were Hispanic, and 1034 (85.6%) were vaccinated (Table 1). Compared to the total sampled population, respondents were more often older, female, and White (eAppendix 2).

Cluster Membership

Four clusters were identified from 1183 (97.9%) participants who provided complete responses to 6 items assessing thoughts and feelings about COVID-19 infection and vaccines (Table 2). Of the 1183 respondents, 375 (31.7%) were Concerned Believers (cluster 1), 336 (28.4%) were Unconcerned Believers (cluster 2), 298 (25.2%) were Concerned Ambivalents (cluster 3), and 174 (14.7%) were Unconcerned Disbelievers (cluster 4). The Concerned Believers were moderately/ very concerned about COVID-19 infection (96.0%) and becoming very ill from infection (94.6%), believed the vaccine was moderately/very effective in preventing COVID-19 infection (100%) and severe illness or death from infection (98.7%), and had slight concern about short-term AEs (92.6%) or long-term complications (92.0%) from the vaccine. The Unconcerned Believers had no/slight concern about COVID-19 infection (76.5%) or becoming very ill (79.2%), believed the vaccine was effective in preventing infection (82.4%) and severe illness and death (83.6%), and had no/slight concern about short-term AEs (94.0%) or long-term complications (87.2%) from the vaccine. The Concerned Ambivalents were moderately/ very concerned about COVID-19 infection (94.3%) and becoming very ill (93.6%), believed the vaccine was moderately/very effective in preventing infection (86.6%) and severe illness or death (86.9%), and were moderately/very concerned about short-term AEs (81.9%) or long-term complications (89.3%) from the vaccine. The Unconcerned Disbelievers had no/slight concern about COVID-19 infection (90.8%) and becoming very ill (88.6%), believed the vaccine was not at all/slightly effective in preventing infection (90.3%) and severe illness or death (87.4%), and were moderately/very concerned about short-term AEs (52.8%) or long-term complications (75.9%) from the vaccine.

Cluster Membership

Respondent age, race and ethnicity, and political viewpoints differed significantly by cluster (P < .001). Compared with the other clusters, the Concerned Believer cluster was older (55.5% age ≥ 65 years vs 16.7%-48.0%) and more frequently reported liberal political views (28.8% vs 4.6%-15.1%). In contrast, the Unconcerned Disbeliever cluster was younger (83.4% age ≤ 64 years vs 44.5%-56.8%) and more frequently reported conservative political views (37.9% vs 17.1%-26.8%) than the other clusters. Whereas the Concerned Ambivalent cluster had the highest proportion of Black (37.7%) and the lowest proportion of White respondents (57.6%), the Unconcerned Disbelievers cluster had the lowest proportion of Black respondents (14.5%) and the highest proportion of White respondents (77.9%). The Unconcerned Disbelievers cluster were significantly less likely to trust COVID-19 vaccine information from any source and to believe those close to them wanted them to get vaccinated.

Association of Cluster Membership and COVID-19 Vaccination

COVID-19 vaccination rates varied more than 3-fold (P < .001) by cluster, with 29.9% of Unconcerned Disbelievers, 93.3% of Concerned Ambivalents, 93.5% of Unconcerned Believers, and 98.9% of Concerned Believers reporting being vaccinated. (Figure). Cluster membership was independently associated with vaccination, with adjusted odds ratios (AORs) of 12.0 (95% CI, 6.1-23.8) for the Concerned Ambivalent, 13.0 (95% CI, 6.9-24.5) for Unconcerned Believer, and 48.6 (95% CI, 15.5-152.1) for Concerned Believer clusters (Table 3). Respondent trust in COVID-19 vaccine information from their VA HCP (AOR 2.1; 95% CI, 1.6-2.8) and the CDC (AOR 1.6; 95% CI, 1.2-2.1) were independently associated with vaccination status, while the remaining respondent sociodemographic or personal characteristics were not.

Qualitative Interview Participants

A 49-participant convenience sample completed interviews, including 30 Concerned Ambivalent, 17 Unconcerned Disbeliever, and 2 Unconcerned Believer respondents cluster. The data were not calculated for Unconcerned Believers due to the small sample size. Interview participants were more likely to be younger, female, non-Hispanic, White, less educated, and more politically conservative than the questionnaire respondents as a whole (Appendix). The vaccination rate for the interview participants was 73.5%, ranging from 29.9% in the Unconcerned Disbeliever to 93.3% in the Concerned Ambivalent cluster. Qualitative themes and participant quotes for Concerned Ambivalent and Unconcerned Disbeliever respondents are in eAppendix 3.

Motivations. Wanting personal protection from becoming infected or severely ill from COVID-19 (63.8%), caregiver wanting to protect others (17.0%), and employment vaccine requirements (14.9%) were frequent motivations for vaccination. Whereas personal protection (90.0%) and protection of others (23.3%) were identified more frequently in the Concerned Ambivalents cluster, employment vaccine requirements (35.3%) were more frequently identified in the Unconcerned Disbelievers cluster.

Hesitancies or concerns. Lack of sufficient information related to rapid vaccine development (55.3%), vaccine AEs (38.3%), and low confidence in vaccine efficacy (23.4%) were frequent concerns or hesitancies about vaccination. Unconcerned Disbelievers expressed higher levels of concern about the vaccine’s rapid development (82.4%), low perceived vaccine efficacy (47.1%), and a lack of trust in governmental vaccine promotion (23.5%) than did the Concerned Ambivalents.

Overcoming concerns. Not wanting to get sick or die from infection coupled with an understanding that vaccine benefits exceed risks (23.4%) and receiving information from a trusted source (10.6%) were common ways of overcoming concerns for vaccination. Although the Unconcerned Disbelievers infrequently identified reasons for overcoming concerns, they identified employment requirements (17.6%) as a reason for vaccination despite concerns. They also identified seeing others with positive vaccine experiences and pressure from family or friends as ways of overcoming concerns (11.8% each).

Social influences. Family members or partners (38.3%), personal opinions (38.3%), and HCPs (23.4%) were frequent social influences for vaccination. Concerned Ambivalents mentioned family members and partners (46.7%), HCPs (26.7%), and friends (20.0%) as common influences, while Unconcerned Disbelievers more frequently relied on their opinion (41.2%) and quoted specific scientifically reputable data sources (17.6%) to guide vaccine decision-making, although it is unclear whether these sources were accessed directly or if this information was obtained indirectly through scientifically unvetted data platforms.

Practical factors. Most participants had positive vaccination experiences (68.1%), determined mainly by the Concerned Ambivalents (90.0%), who were more highly vaccinated. Barriers to vaccination were reported by 9 (19.1%) participants, driven by those in the Concerned Ambivalent cluster (26.7%). Eight (17.0%) participants suggested improvements for vaccination processes, with similar overall reporting frequencies across clusters.

COVID-19 boosters and variants. Wanting continued protection from COVID-19 (36.2%), recommendations from a doctor or trusted source (17.0%), and news about emerging variants (10.6%) were frequent motivations for receiving a vaccine booster (eAppendix 4). These motivations were largely driven by the Concerned Ambivalents, of whom 25 of 30 were booster eligible and 24 received a booster dose. Belief that boosters were unnecessary (8.5%), concerns about efficacy (6.4%), and concerns about AEs (6.4%) were frequently identified hesitancies. These concerns were expressed largely by the Unconcerned Disbelievers, of whom 7 of 17 were booster dose eligible, but only 1 received a dose.

Evolving knowledge about variants was not a major concern overall and did not change existing opinions about the vaccine (36.2%). Concerned Ambivalents believed vaccination provided extra protection against variants (36.7%) and the emergence of variants served as a reminder of the ongoing pandemic (30.0%). In contrast, Unconcerned Disbelievers believed that the threat of variants was overblown (35.3%) and mutations are to be expected (17.6%).

Discussion

This study used a complementary mixed-methods approach to understand the motivations, hesitancies, and social and practical drivers of COVID-19 vaccine uptake among VA beneficiaries. Our quantitative analyses identified 4 distinct clusters based on respondents’ opinions on COVID-19 infection severity and vaccine effectiveness and safety. Veterans in 3 clusters were 12 to 49 times more likely to be vaccinated than those in the remaining cluster, even when controlling for baseline respondent characteristics and level of trust in credible sources of COVID-19 information. The observed vaccination rate of nearly 86% was higher than the contemporaneous national average of 62% for vaccine-eligible individuals, likely reflecting the comprehensive VA vaccine promotion strategies tailored to a patient demographic with a high COVID-19 risk profile.^2,10

This cluster analyses demonstrated the importance of thoughts and feelings about COVID-19 infection and vaccination as influential social and behavioral drivers of vaccine uptake. These opinions help explain the strong association between cluster membership and vaccination status in this multivariable modeling. The cluster composition was consistent with findings from studies of nonveteran populations that identified perceived vulnerability to COVID-19 infection, beliefs in vaccine effectiveness, and adherence with protective behaviors during the pandemic as contributors to vaccine uptake.^13,33 Qualitative themes showed that personal protection, protecting others, and vaccine mandates were frequent motivators for vaccination. Whereas protection of self and others from COVID-19 infection were more often expressed by the highly vaccinated Concerned Ambivalents, employment and travel vaccine mandates were more often identified by Unconcerned Disbelievers, who had a lower vaccination rate. Among Unconcerned Disbelievers, an employer vaccine requirement was the most frequent qualitative theme for overcoming vaccination concerns.

In addition to cluster membership, our modeling showed that trust in local VA HCPs and the CDC were independently associated with COVID-19 vaccination, which has been found in prior research.²⁰ This qualitative analyses regarding vaccine hesitancy identified trust-related concerns that were more frequently expressed by Unconcerned Disbelievers than Concerned Ambivalents. Concerns included the rapid development of the vaccines potentially limiting the generation of scientifically sound effectiveness and safety data, and potential biases involving the entities promoting vaccine uptake.

Whereas the Concerned Believers, Unconcerned Believers, and Concerned Ambivalents all had high COVID-19 vaccination rates (≥ 93%), the decision-making pathways to vaccine uptake likely differ by their concerns about COVID-19 infection and perceptions of vaccine safety and effectiveness. For example, this mixed-methods analysis consistently showed that people in the Concerned Ambivalent cluster were positively motivated by concerns about COVID-19 infection and severity and beliefs about vaccine effectiveness that were tempered by concerns about vaccine AEs. For this cluster, their frequent thematic expression that the benefits of the vaccine exceed the risks, and the positive social influences of family, friends, and HCPs may explain their high vaccination rate.

Such insights into how the patterns of COVID-19–related thoughts and feelings vary across clusters can be used to design interventions to encourage initial and booster doses of COVID-19 vaccines. For example, messaging that highlights the infectivity and severity of COVID-19 and the potential for persistent negative health outcomes associated with long COVID could reinforce the beliefs of Concerned Believers and Concerned Ambivalents, and such messaging could also be used as a targeted intervention for Unconcerned Believers who expressed fewer concerns about the health consequences of COVID-19.23 Likewise, messaging about the safety profile of COVID-19 vaccines may reduce vaccine hesitancy for Concerned Ambivalents. Importantly, purposeful attention to health equity, community engagement, and involvement of racially diverse HCPs in patient discussions represent successful strategies to increase COVID-19 vaccine uptake among Black individuals, who were disproportionately represented in the Concerned Ambivalent cluster and may possess higher levels of mistrust due to racism experienced within the health care system.²⁴

Our findings suggest that the greatest challenge for overcoming vaccine hesitancy is for individuals in the suboptimally vaccinated (30%) Unconcerned Disbeliever cluster. These individuals had low levels of concern about COVID-19 infection and severity, high levels of concern about vaccine safety, low perceived vaccine effectiveness, and low levels of trust in all information sources about COVID-19. While the Unconcerned Disbelievers cited scientifically reputable data sources, we were unable to verify whether participants accessed these reputable sources of information directly or obtained such information indirectly through potentially biased online sources. Nearly half of this cluster trusted their VA HCP and believed their community or religious leaders would want them to get vaccinated. This qualitative analyses found that Unconcerned Disbelievers relied on personal beliefs for vaccine decision-making more than Concerned Ambivalents. While Unconcerned Disbelievers were less likely to be socially influenced by family, friends, or religious leaders, they still acknowledged some impact from these sources. These findings suggest that addressing vaccine hesitancy among Unconcerned Disbelievers may require a multifaceted approach that respects their reliance on personal research while also leveraging the potential social influences. This approach supports the promising, previously reported practices of harnessing the social influences of HCPs and other community and religious leaders to promote vaccine uptake among Unconcerned Disbelievers.^34,35 One evidence-based approach to effectively change patient health care behaviors is through motivational interviewing strategies that use open-ended questions, nonjudgmental interactions, and collaborative decision-making when discussing the risks and benefits of vaccination.^21,22

Limitations

This study was conducted at a single VA health care facility and our sampling technique was nonrandom, suggesting that these results may not be generalizable to all veterans or non-VA patient populations. The 21% questionnaire response rate could have introduced selection bias into the respondent sample. All questionnaire data were self-reported, including vaccination status. Finally, the qualitative interviews consisted of a small number of unvaccinated individuals in 2 clusters (ie, Concerned Ambivalents and Unconcerned Disbelievers) and may not have reached thematic saturation in these subgroups.

Conclusions

Quantitative analyses identified 4 clusters based on individual thoughts and feelings about COVID-19 infection and vaccines. Cluster membership and levels of trust in COVID-19 information sources were independently associated with vaccination. Understanding the quantitative patterns of thoughts and beliefs across clusters, enriched by common qualitative themes for vaccine hesitancy, help inform tailored interventions to augment COVID-19 vaccine uptake and highlight the importance of targeted, trust-based communication and culturally sensitive interventions to enhance vaccine uptake across diverse populations.

The SARS-CoV-2 virus has resulted in > 778 million reported COVID-19 cases and > 7 million deaths worldwide. ¹ About 70% of the eligible US population has completed a primary COVID-19 vaccination series, yet only 17% have received an updated bivalent booster dose.² These immunization rates fall below the World Health Organization (WHO) target of 70%.³

Early in the pandemic, US Department of Veterans Affairs (VA) vaccination rates ranged from 46% to 71%.^4,5 Ensuring a high level of COVID-19 vaccination in the largest integrated US health care system aligns with the VA priority to provide high-quality, evidence-based care to a patient population that is older and has more comorbidities than the overall US population.^6-9

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite availability of vaccination service,” is a major contributor to suboptimal vaccination rates.^10-13 Previous studies used cluster analyses to identify the unique combinations of behavioral and social factors responsible for COVID-19 vaccine hesitancy.^10,11 Lack of perceived vaccine effectiveness and low perceived risk of the health consequences from COVID-19 infection were frequently identified in clusters where patients had the lowest intent for vaccination.^10,11 Similarly, low trust in health care practitioners (HCPs), government, and pharmaceutical companies diminished intent for vaccination in these clusters.¹⁰ These quantitative studies were limited by their exclusive focus on unvaccinated individuals, reliance on self-reported intent, and lack of assessment of a health care system with a COVID-19 vaccine delivery program designed to overcome barriers to health care access, such as the VA.

Prior qualitative studies of vaccine uptake in distinct veteran subgroups (ie, unhoused and in VA facilities with low vaccination rates) demonstrated that overriding medical priorities among the unhoused and vaccine safety concerns were associated with decreased vaccine uptake, and positive perceptions of HCPs and the health care system were associated with increased vaccine uptake.^11,12 However, these studies were conducted during periods of greater COVID-19 vaccine availability and acceptance, and prior to booster recommendations.^4,12,13

This mixed-methods quality improvement (QI) project assessed the barriers and facilitators of COVID-19 vaccination among veterans receiving primary care at a single VA health care facility. We assessed whether unique patient clusters could be identified based on COVID-19–related and vaccine-related thoughts and feelings and whether cluster membership was associated with COVID-19 vaccination. This analysis also explored how individuals’ beliefs and trust shaped motivations and hesitancies for vaccine uptake in quantitatively derived clusters with varying vaccination rates.

Methods

This QI project was conducted at the VA Pittsburgh Healthcare System (VAPHS), a tertiary care facility serving > 75,000 veterans in Pennsylvania, West Virginia, and Ohio. The VAPHS Institutional Review Board determined this QI study was exempt from review.^14-17 Participation was voluntary and had no bearing on VA health care or benefits. Financial support for the project, including key personnel and participant compensation, was provided by VAPHS. We followed the STROBE reporting guideline for cross-sectional studies and the COREQ checklist for qualitative research.^18,19

Quantitative Survey

The 32,271 veterans assigned to a VAPHS primary care HCP, effective April 1, 2020, were eligible. To ensure representation of subgroups underrecognized in research and/or QI projects, the sample included all 1980 female patients at VAPHS and a random sample of 500 White and 500 Hispanic and/or non-White men within 4 age categories (< 50, 50-64, 65-84, and > 84 years). For the < 50 years or > 84 years categories, all Hispanic and/or non-White men were included due to small sample sizes.^20-22 The nonrandom sampling frame comprised 1708 Hispanic and/or non-White men and 2000 White men. After assigning the 5688 potentially eligible individuals a unique identifier, 31 opted out, resulting in a final sample of 5657 individuals.

The 5657 individuals received a letter requesting their completion of a future questionnaire about COVID-19 infection and vaccines. An electronic Qualtrics questionnaire link was emailed to 3221 individuals; nonresponders received 2 follow-up email reminders. For the 2436 veterans without an email address on file, trained interviewers conducted phone surveys and entered responses. Those patients who completed the questionnaire could enter a drawing to win 1 of 100 cash prizes valued at $100. We collected questionnaire data from July to September 2021.

Questionnaire Items

We constructed a 60-item questionnaire based on prior research on COVID-19 vaccine hesitancy and the WHO Guidebook for Immunization Programs and Implementing Partners.^4,23-25 The WHO Guidebook comprises survey items organized within 4 domains reflecting the behavioral and social determinants of vaccination: thoughts and feelings; social processes; motivation and hesitancy; and practical factors.²³

Sociodemographic, clinical, and personal characteristics. The survey assessed respondent ethnicity and race and used these data to create a composite race and ethnicity variable. Highest educational level was also attained using 8 response options. The survey also assessed prior COVID-19 infection; prior receipt of vaccines for influenza, pneumonia, tetanus, or shingles; and presence of comorbidities that increase the risk of severe COVID-19 infection. We used administrative data from the VA Corporate Data Warehouse to determine respondent age, sex, geographic residence (urban, rural), and to fill in missing self-reported data on sex (n = 4) and ethnicity and race (n = 12). The survey assessed political views using a 5-point Likert scale (1, very liberal; 5, very conservative) and was collapsed into 3 categories (ie, very conservative or conservative, moderate, very liberal or liberal), with prefer not to answer reported separately

COVID-19 infection and vaccine. We asked veterans if they had ever been infected with COVID-19, whether they had been offered and/or received a COVID-19 vaccine, and type (Pfizer, Moderna, or Johnson & Johnson), and number of doses received. Positive vaccination status was defined as the receipt of ≥ 1 dose of a COVID-19 vaccine approved by the US Food and Drug Administration.

COVID-19 opinions. Respondents were asked about perceived risk of COVID-19 infection and related health outcomes, as well as beliefs about COVID-19 vaccines, using a 4-point Likert scale for all items: (1, not at all concerned; 4, very concerned). Respondents were asked about concerns related to COVID-19 infection and severe illness. They also were asked about vaccine-related short-term adverse effects (AEs) and long-term complications. Respondents were asked how effective they believed COVID-19 vaccines were at preventing infection, serious illness, or death. Unvaccinated and vaccinated veterans were asked similar items, with a qualifier of “before getting vaccinated…” for those who were vaccinated.

Social processes. Respondents were asked to rate their level of trust in various sources of COVID-19 vaccine information using a 4-point Likert scale (1, trust not at all; 4, trust very much). Respondents were asked whether community or religious leaders or close family or friends wanted them to get vaccinated (yes, no, or unsure).

Practical factors. Respondents were asked to rate the logistical difficulty of getting vaccinated or trying to get vaccinated using a 4-point Likert scale (1, not at all; 4, extremely).

Participants

Respondents were asked to participate in a follow-up qualitative interview. Among 293 participants who agreed, we sampled all 86 unvaccinated individuals regardless of cluster assignment, a random sample of 88 individuals in the cluster with the lowest vaccination rate, and all 33 vaccinated individuals in the cluster with the second-lowest vaccination rate. Forty-nine veterans completed qualitative interviews.

Two research staff trained in qualitative research completed telephone interviews, averaging 16.5 minutes (March to May 2022), using semistructured scripts to elicit vaccine-related motivations, hesitancies, or concerns. Interviews were recorded, transcribed, and deidentified. Participants provided written consent for recording and received $50 cash-equivalent compensation for interview completion.

Qualitative Interview Script

The interview script consisted of open-ended questions related to vaccine uptake across WHO domains.²³ Both unvaccinated and vaccinated respondents were asked similar questions and customized questions about boosters for the vaccinated subgroup. To assess motivations and hesitancies, respondents were asked how they made their decisions about vaccination and what they considered when deciding. Vaccinated participants were asked about motivations and overcoming concerns. Unvaccinated respondents were asked about reasons for concern. To assess social processes, the interviewers asked participants whose opinion or counsel they trusted when deciding whether to get vaccinated. Questions also focused on positive experiences and vaccination barriers. Vaccinated participants were asked what could have improved their vaccination experiences. Finally, the interviewers asked participants who received a complete primary vaccine series about their motivations and plans related to booster vaccines, and whether information about emerging COVID-19 variants influenced their decisions.

Data Analyses

This analysis used X² and Fisher exact tests to assess the associations among respondent characteristics, questionnaire responses, vaccination status, and cluster membership. Items phrased similarly were handled in a similar fashion for vaccinated and unvaccinated respondents.

Cluster analysis assessed the possible groupings in responses to the quantitative questionnaire items focused on thoughts and feelings about COVID-19 infection risk and severity, vaccine effectiveness, and vaccine safety. This analysis treated the items’ ordinal response categories as continuous. We performed factor analysis using principal component analysis to explore dimension reduction and account for covariance between items. Two principal components were calculated and applied k-means clustering, determining the number of clusters through agreement from the elbow, gap statistic, and silhouette methods.²⁶ Each cluster was named based on its unique pattern of responses to the items used to define them (eAppendix 1).

Multivariable logistic regression analyses assessed the independent association between cluster membership as the independent measure and vaccination status as the dependent measure, adjusting for respondent sociodemographic and personal characteristics and 2 measures of trust (ie, local VA HCP and the CDC). We selected these trust measures because they represent objective sources of medical information and were independently associated with COVID-19 vaccination status in a logistic regression model comprising all 6 trust items assessed.

This study defined statistical significance as a 2-tailed P value < .05. SAS 9.4 was used for all statistical analyses and Python 3.7.4 and the Scikit-learn package for cluster analyses.²⁷ For qualitative analyses, this study used an inductive thematic approach guided by conventional qualitative content analysis, NVivo 12 Plus for Windows to code and analyze interview transcripts.^28,29 We created an initial codebook based on 10 transcripts that were selected for high complexity and represented cluster membership and vaccination status.^30,31 After 2 qualitative staff developed the initial codebook, 11 of 49 (22%) transcripts were independently coded by a primary and secondary coder to ensure consistent code application. Both coders reviewed the cocoded transcripts and resolved all discrepancies through negotiated consensus.³² After the cocoding process was complete, the primary coder coded the remaining transcripts. The primary and secondary coder met as needed to review and discuss any questions that arose during the primary coder’s work.

Results

Of 5657 eligible participants, 1208 (21.4%) completed a questionnaire. Overall, 674 (55.8%) were aged < 65 years, 530 (43.9%) were women, 828 (68.5%) were non-Hispanic White, 303 (25.1%) were Black, and 47 (3.9%) were Hispanic, and 1034 (85.6%) were vaccinated (Table 1). Compared to the total sampled population, respondents were more often older, female, and White (eAppendix 2).

Cluster Membership

Four clusters were identified from 1183 (97.9%) participants who provided complete responses to 6 items assessing thoughts and feelings about COVID-19 infection and vaccines (Table 2). Of the 1183 respondents, 375 (31.7%) were Concerned Believers (cluster 1), 336 (28.4%) were Unconcerned Believers (cluster 2), 298 (25.2%) were Concerned Ambivalents (cluster 3), and 174 (14.7%) were Unconcerned Disbelievers (cluster 4). The Concerned Believers were moderately/ very concerned about COVID-19 infection (96.0%) and becoming very ill from infection (94.6%), believed the vaccine was moderately/very effective in preventing COVID-19 infection (100%) and severe illness or death from infection (98.7%), and had slight concern about short-term AEs (92.6%) or long-term complications (92.0%) from the vaccine. The Unconcerned Believers had no/slight concern about COVID-19 infection (76.5%) or becoming very ill (79.2%), believed the vaccine was effective in preventing infection (82.4%) and severe illness and death (83.6%), and had no/slight concern about short-term AEs (94.0%) or long-term complications (87.2%) from the vaccine. The Concerned Ambivalents were moderately/ very concerned about COVID-19 infection (94.3%) and becoming very ill (93.6%), believed the vaccine was moderately/very effective in preventing infection (86.6%) and severe illness or death (86.9%), and were moderately/very concerned about short-term AEs (81.9%) or long-term complications (89.3%) from the vaccine. The Unconcerned Disbelievers had no/slight concern about COVID-19 infection (90.8%) and becoming very ill (88.6%), believed the vaccine was not at all/slightly effective in preventing infection (90.3%) and severe illness or death (87.4%), and were moderately/very concerned about short-term AEs (52.8%) or long-term complications (75.9%) from the vaccine.

Cluster Membership

Respondent age, race and ethnicity, and political viewpoints differed significantly by cluster (P < .001). Compared with the other clusters, the Concerned Believer cluster was older (55.5% age ≥ 65 years vs 16.7%-48.0%) and more frequently reported liberal political views (28.8% vs 4.6%-15.1%). In contrast, the Unconcerned Disbeliever cluster was younger (83.4% age ≤ 64 years vs 44.5%-56.8%) and more frequently reported conservative political views (37.9% vs 17.1%-26.8%) than the other clusters. Whereas the Concerned Ambivalent cluster had the highest proportion of Black (37.7%) and the lowest proportion of White respondents (57.6%), the Unconcerned Disbelievers cluster had the lowest proportion of Black respondents (14.5%) and the highest proportion of White respondents (77.9%). The Unconcerned Disbelievers cluster were significantly less likely to trust COVID-19 vaccine information from any source and to believe those close to them wanted them to get vaccinated.

Association of Cluster Membership and COVID-19 Vaccination

COVID-19 vaccination rates varied more than 3-fold (P < .001) by cluster, with 29.9% of Unconcerned Disbelievers, 93.3% of Concerned Ambivalents, 93.5% of Unconcerned Believers, and 98.9% of Concerned Believers reporting being vaccinated. (Figure). Cluster membership was independently associated with vaccination, with adjusted odds ratios (AORs) of 12.0 (95% CI, 6.1-23.8) for the Concerned Ambivalent, 13.0 (95% CI, 6.9-24.5) for Unconcerned Believer, and 48.6 (95% CI, 15.5-152.1) for Concerned Believer clusters (Table 3). Respondent trust in COVID-19 vaccine information from their VA HCP (AOR 2.1; 95% CI, 1.6-2.8) and the CDC (AOR 1.6; 95% CI, 1.2-2.1) were independently associated with vaccination status, while the remaining respondent sociodemographic or personal characteristics were not.

Qualitative Interview Participants

A 49-participant convenience sample completed interviews, including 30 Concerned Ambivalent, 17 Unconcerned Disbeliever, and 2 Unconcerned Believer respondents cluster. The data were not calculated for Unconcerned Believers due to the small sample size. Interview participants were more likely to be younger, female, non-Hispanic, White, less educated, and more politically conservative than the questionnaire respondents as a whole (Appendix). The vaccination rate for the interview participants was 73.5%, ranging from 29.9% in the Unconcerned Disbeliever to 93.3% in the Concerned Ambivalent cluster. Qualitative themes and participant quotes for Concerned Ambivalent and Unconcerned Disbeliever respondents are in eAppendix 3.

Motivations. Wanting personal protection from becoming infected or severely ill from COVID-19 (63.8%), caregiver wanting to protect others (17.0%), and employment vaccine requirements (14.9%) were frequent motivations for vaccination. Whereas personal protection (90.0%) and protection of others (23.3%) were identified more frequently in the Concerned Ambivalents cluster, employment vaccine requirements (35.3%) were more frequently identified in the Unconcerned Disbelievers cluster.

Hesitancies or concerns. Lack of sufficient information related to rapid vaccine development (55.3%), vaccine AEs (38.3%), and low confidence in vaccine efficacy (23.4%) were frequent concerns or hesitancies about vaccination. Unconcerned Disbelievers expressed higher levels of concern about the vaccine’s rapid development (82.4%), low perceived vaccine efficacy (47.1%), and a lack of trust in governmental vaccine promotion (23.5%) than did the Concerned Ambivalents.

Overcoming concerns. Not wanting to get sick or die from infection coupled with an understanding that vaccine benefits exceed risks (23.4%) and receiving information from a trusted source (10.6%) were common ways of overcoming concerns for vaccination. Although the Unconcerned Disbelievers infrequently identified reasons for overcoming concerns, they identified employment requirements (17.6%) as a reason for vaccination despite concerns. They also identified seeing others with positive vaccine experiences and pressure from family or friends as ways of overcoming concerns (11.8% each).

Social influences. Family members or partners (38.3%), personal opinions (38.3%), and HCPs (23.4%) were frequent social influences for vaccination. Concerned Ambivalents mentioned family members and partners (46.7%), HCPs (26.7%), and friends (20.0%) as common influences, while Unconcerned Disbelievers more frequently relied on their opinion (41.2%) and quoted specific scientifically reputable data sources (17.6%) to guide vaccine decision-making, although it is unclear whether these sources were accessed directly or if this information was obtained indirectly through scientifically unvetted data platforms.

Practical factors. Most participants had positive vaccination experiences (68.1%), determined mainly by the Concerned Ambivalents (90.0%), who were more highly vaccinated. Barriers to vaccination were reported by 9 (19.1%) participants, driven by those in the Concerned Ambivalent cluster (26.7%). Eight (17.0%) participants suggested improvements for vaccination processes, with similar overall reporting frequencies across clusters.

COVID-19 boosters and variants. Wanting continued protection from COVID-19 (36.2%), recommendations from a doctor or trusted source (17.0%), and news about emerging variants (10.6%) were frequent motivations for receiving a vaccine booster (eAppendix 4). These motivations were largely driven by the Concerned Ambivalents, of whom 25 of 30 were booster eligible and 24 received a booster dose. Belief that boosters were unnecessary (8.5%), concerns about efficacy (6.4%), and concerns about AEs (6.4%) were frequently identified hesitancies. These concerns were expressed largely by the Unconcerned Disbelievers, of whom 7 of 17 were booster dose eligible, but only 1 received a dose.

Evolving knowledge about variants was not a major concern overall and did not change existing opinions about the vaccine (36.2%). Concerned Ambivalents believed vaccination provided extra protection against variants (36.7%) and the emergence of variants served as a reminder of the ongoing pandemic (30.0%). In contrast, Unconcerned Disbelievers believed that the threat of variants was overblown (35.3%) and mutations are to be expected (17.6%).

Discussion

This study used a complementary mixed-methods approach to understand the motivations, hesitancies, and social and practical drivers of COVID-19 vaccine uptake among VA beneficiaries. Our quantitative analyses identified 4 distinct clusters based on respondents’ opinions on COVID-19 infection severity and vaccine effectiveness and safety. Veterans in 3 clusters were 12 to 49 times more likely to be vaccinated than those in the remaining cluster, even when controlling for baseline respondent characteristics and level of trust in credible sources of COVID-19 information. The observed vaccination rate of nearly 86% was higher than the contemporaneous national average of 62% for vaccine-eligible individuals, likely reflecting the comprehensive VA vaccine promotion strategies tailored to a patient demographic with a high COVID-19 risk profile.^2,10

This cluster analyses demonstrated the importance of thoughts and feelings about COVID-19 infection and vaccination as influential social and behavioral drivers of vaccine uptake. These opinions help explain the strong association between cluster membership and vaccination status in this multivariable modeling. The cluster composition was consistent with findings from studies of nonveteran populations that identified perceived vulnerability to COVID-19 infection, beliefs in vaccine effectiveness, and adherence with protective behaviors during the pandemic as contributors to vaccine uptake.^13,33 Qualitative themes showed that personal protection, protecting others, and vaccine mandates were frequent motivators for vaccination. Whereas protection of self and others from COVID-19 infection were more often expressed by the highly vaccinated Concerned Ambivalents, employment and travel vaccine mandates were more often identified by Unconcerned Disbelievers, who had a lower vaccination rate. Among Unconcerned Disbelievers, an employer vaccine requirement was the most frequent qualitative theme for overcoming vaccination concerns.

In addition to cluster membership, our modeling showed that trust in local VA HCPs and the CDC were independently associated with COVID-19 vaccination, which has been found in prior research.²⁰ This qualitative analyses regarding vaccine hesitancy identified trust-related concerns that were more frequently expressed by Unconcerned Disbelievers than Concerned Ambivalents. Concerns included the rapid development of the vaccines potentially limiting the generation of scientifically sound effectiveness and safety data, and potential biases involving the entities promoting vaccine uptake.

Whereas the Concerned Believers, Unconcerned Believers, and Concerned Ambivalents all had high COVID-19 vaccination rates (≥ 93%), the decision-making pathways to vaccine uptake likely differ by their concerns about COVID-19 infection and perceptions of vaccine safety and effectiveness. For example, this mixed-methods analysis consistently showed that people in the Concerned Ambivalent cluster were positively motivated by concerns about COVID-19 infection and severity and beliefs about vaccine effectiveness that were tempered by concerns about vaccine AEs. For this cluster, their frequent thematic expression that the benefits of the vaccine exceed the risks, and the positive social influences of family, friends, and HCPs may explain their high vaccination rate.

Such insights into how the patterns of COVID-19–related thoughts and feelings vary across clusters can be used to design interventions to encourage initial and booster doses of COVID-19 vaccines. For example, messaging that highlights the infectivity and severity of COVID-19 and the potential for persistent negative health outcomes associated with long COVID could reinforce the beliefs of Concerned Believers and Concerned Ambivalents, and such messaging could also be used as a targeted intervention for Unconcerned Believers who expressed fewer concerns about the health consequences of COVID-19.23 Likewise, messaging about the safety profile of COVID-19 vaccines may reduce vaccine hesitancy for Concerned Ambivalents. Importantly, purposeful attention to health equity, community engagement, and involvement of racially diverse HCPs in patient discussions represent successful strategies to increase COVID-19 vaccine uptake among Black individuals, who were disproportionately represented in the Concerned Ambivalent cluster and may possess higher levels of mistrust due to racism experienced within the health care system.²⁴

Our findings suggest that the greatest challenge for overcoming vaccine hesitancy is for individuals in the suboptimally vaccinated (30%) Unconcerned Disbeliever cluster. These individuals had low levels of concern about COVID-19 infection and severity, high levels of concern about vaccine safety, low perceived vaccine effectiveness, and low levels of trust in all information sources about COVID-19. While the Unconcerned Disbelievers cited scientifically reputable data sources, we were unable to verify whether participants accessed these reputable sources of information directly or obtained such information indirectly through potentially biased online sources. Nearly half of this cluster trusted their VA HCP and believed their community or religious leaders would want them to get vaccinated. This qualitative analyses found that Unconcerned Disbelievers relied on personal beliefs for vaccine decision-making more than Concerned Ambivalents. While Unconcerned Disbelievers were less likely to be socially influenced by family, friends, or religious leaders, they still acknowledged some impact from these sources. These findings suggest that addressing vaccine hesitancy among Unconcerned Disbelievers may require a multifaceted approach that respects their reliance on personal research while also leveraging the potential social influences. This approach supports the promising, previously reported practices of harnessing the social influences of HCPs and other community and religious leaders to promote vaccine uptake among Unconcerned Disbelievers.^34,35 One evidence-based approach to effectively change patient health care behaviors is through motivational interviewing strategies that use open-ended questions, nonjudgmental interactions, and collaborative decision-making when discussing the risks and benefits of vaccination.^21,22

Limitations

This study was conducted at a single VA health care facility and our sampling technique was nonrandom, suggesting that these results may not be generalizable to all veterans or non-VA patient populations. The 21% questionnaire response rate could have introduced selection bias into the respondent sample. All questionnaire data were self-reported, including vaccination status. Finally, the qualitative interviews consisted of a small number of unvaccinated individuals in 2 clusters (ie, Concerned Ambivalents and Unconcerned Disbelievers) and may not have reached thematic saturation in these subgroups.

Conclusions

Quantitative analyses identified 4 clusters based on individual thoughts and feelings about COVID-19 infection and vaccines. Cluster membership and levels of trust in COVID-19 information sources were independently associated with vaccination. Understanding the quantitative patterns of thoughts and beliefs across clusters, enriched by common qualitative themes for vaccine hesitancy, help inform tailored interventions to augment COVID-19 vaccine uptake and highlight the importance of targeted, trust-based communication and culturally sensitive interventions to enhance vaccine uptake across diverse populations.

TOPLINE:

A single dose of the recombinant respiratory syncytial virus (RSV) vaccine demonstrates effectiveness against infections and associated hospitalizations in veterans aged 60 years or older during the 2023-2024 respiratory illness season. This protection extends across age groups and immunocompromised individuals.

METHODOLOGY:

• Researchers conducted a target trial emulation study to evaluate the real-world effectiveness of a single dose of recombinant RSV vaccine (RSVPreF3 or RSVpreF) among veterans enrolled in the Veterans Health Administration in the United States between September 1 and December 31, 2023.

• They analyzed 146,852 vaccinated veterans (69.2%, RSVPreF; 29.9%, RSVPreF3) propensity matched with 582,936 unvaccinated ones (median age, ~76 years; ~94% men; immunocompromised individuals, 11.2%) who were followed up for a median of 124 days.

• The primary outcome was any positive RSV test result obtained from day 14 after vaccination.

• The secondary outcomes were RSV-associated emergency department or urgent care visits, hospitalizations, intensive care unit (ICU) admissions, and death.

TAKEAWAY:

• Vaccine effectiveness against documented RSV infections was 78.1% (95% CI, 72.6-83.5), with incidence rates of infections lower in the vaccinated group than in the unvaccinated group (1.7 vs 7.3 per 1000 person-years).

• Likewise, vaccine effectiveness against RSV-associated emergency department or urgent care visits was 78.7% (95% CI, 72.2-84.8), with rates of infections lower in the vaccinated group than in the unvaccinated group (1.3 vs 5.7 per 1000 person-years).

• Immunocompromised veterans demonstrated a lower vaccine effectiveness of 71.6% (95% CI, 55.4-85.2); however, infection rates remained lower in the vaccinated group than in the unvaccinated group (5.8 vs 19.9 per 1000 person-years).

• Hospitalizations, ICU admission rates, and mortality rates were also lower in the vaccinated group than in the unvaccinated group.

IN PRACTICE:

“These results give confidence that an RSV vaccine for older adults is likely to provide protection against RSV infection and RSV disease, at least in the first season following vaccination,” wrote the author of an accompanying comment.

SOURCE:

The study was funded by the US Department of Veterans Affairs Cooperative Studies Program. It was published online on January 20, 2025, in The Lancet Infectious Diseases (2025 Jan 20. doi:10.1016/S1473-3099(24)00796-5)

LIMITATIONS:

This study did not account for veterans who sought care outside of the Veterans Health Administration. While the study employed rigorous matching to ensure the similarity of demographic, geographic, and clinical characteristics, there could still have been residual confounding. Also, the study was not designed to estimate the protective effect of the vaccine against mild RSV illness.

DISCLOSURES:

This study was supported by the US Department of Veterans Affairs Cooperative Studies Program and funded in part by the US Department of Health and Human Services Biomedical Advanced Research and Development Authority and US Food and Drug Administration. One of the authors reported receiving consulting support from Van-Breemen & Hynes and having a subcontract at Oregon State University for a Patient-Centered Outcomes Research Institute grant. Others reported no conflicts of interest.■

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

A single dose of the recombinant respiratory syncytial virus (RSV) vaccine demonstrates effectiveness against infections and associated hospitalizations in veterans aged 60 years or older during the 2023-2024 respiratory illness season. This protection extends across age groups and immunocompromised individuals.

METHODOLOGY:

• Researchers conducted a target trial emulation study to evaluate the real-world effectiveness of a single dose of recombinant RSV vaccine (RSVPreF3 or RSVpreF) among veterans enrolled in the Veterans Health Administration in the United States between September 1 and December 31, 2023.

• They analyzed 146,852 vaccinated veterans (69.2%, RSVPreF; 29.9%, RSVPreF3) propensity matched with 582,936 unvaccinated ones (median age, ~76 years; ~94% men; immunocompromised individuals, 11.2%) who were followed up for a median of 124 days.

• The primary outcome was any positive RSV test result obtained from day 14 after vaccination.

• The secondary outcomes were RSV-associated emergency department or urgent care visits, hospitalizations, intensive care unit (ICU) admissions, and death.

TAKEAWAY:

• Vaccine effectiveness against documented RSV infections was 78.1% (95% CI, 72.6-83.5), with incidence rates of infections lower in the vaccinated group than in the unvaccinated group (1.7 vs 7.3 per 1000 person-years).

• Likewise, vaccine effectiveness against RSV-associated emergency department or urgent care visits was 78.7% (95% CI, 72.2-84.8), with rates of infections lower in the vaccinated group than in the unvaccinated group (1.3 vs 5.7 per 1000 person-years).

• Immunocompromised veterans demonstrated a lower vaccine effectiveness of 71.6% (95% CI, 55.4-85.2); however, infection rates remained lower in the vaccinated group than in the unvaccinated group (5.8 vs 19.9 per 1000 person-years).

• Hospitalizations, ICU admission rates, and mortality rates were also lower in the vaccinated group than in the unvaccinated group.

IN PRACTICE:

“These results give confidence that an RSV vaccine for older adults is likely to provide protection against RSV infection and RSV disease, at least in the first season following vaccination,” wrote the author of an accompanying comment.

SOURCE:

The study was funded by the US Department of Veterans Affairs Cooperative Studies Program. It was published online on January 20, 2025, in The Lancet Infectious Diseases (2025 Jan 20. doi:10.1016/S1473-3099(24)00796-5)

LIMITATIONS:

This study did not account for veterans who sought care outside of the Veterans Health Administration. While the study employed rigorous matching to ensure the similarity of demographic, geographic, and clinical characteristics, there could still have been residual confounding. Also, the study was not designed to estimate the protective effect of the vaccine against mild RSV illness.

DISCLOSURES:

This study was supported by the US Department of Veterans Affairs Cooperative Studies Program and funded in part by the US Department of Health and Human Services Biomedical Advanced Research and Development Authority and US Food and Drug Administration. One of the authors reported receiving consulting support from Van-Breemen & Hynes and having a subcontract at Oregon State University for a Patient-Centered Outcomes Research Institute grant. Others reported no conflicts of interest.■

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

A single dose of the recombinant respiratory syncytial virus (RSV) vaccine demonstrates effectiveness against infections and associated hospitalizations in veterans aged 60 years or older during the 2023-2024 respiratory illness season. This protection extends across age groups and immunocompromised individuals.

METHODOLOGY:

• Researchers conducted a target trial emulation study to evaluate the real-world effectiveness of a single dose of recombinant RSV vaccine (RSVPreF3 or RSVpreF) among veterans enrolled in the Veterans Health Administration in the United States between September 1 and December 31, 2023.

• They analyzed 146,852 vaccinated veterans (69.2%, RSVPreF; 29.9%, RSVPreF3) propensity matched with 582,936 unvaccinated ones (median age, ~76 years; ~94% men; immunocompromised individuals, 11.2%) who were followed up for a median of 124 days.

• The primary outcome was any positive RSV test result obtained from day 14 after vaccination.

• The secondary outcomes were RSV-associated emergency department or urgent care visits, hospitalizations, intensive care unit (ICU) admissions, and death.

TAKEAWAY:

• Vaccine effectiveness against documented RSV infections was 78.1% (95% CI, 72.6-83.5), with incidence rates of infections lower in the vaccinated group than in the unvaccinated group (1.7 vs 7.3 per 1000 person-years).

• Likewise, vaccine effectiveness against RSV-associated emergency department or urgent care visits was 78.7% (95% CI, 72.2-84.8), with rates of infections lower in the vaccinated group than in the unvaccinated group (1.3 vs 5.7 per 1000 person-years).

• Immunocompromised veterans demonstrated a lower vaccine effectiveness of 71.6% (95% CI, 55.4-85.2); however, infection rates remained lower in the vaccinated group than in the unvaccinated group (5.8 vs 19.9 per 1000 person-years).

• Hospitalizations, ICU admission rates, and mortality rates were also lower in the vaccinated group than in the unvaccinated group.

IN PRACTICE:

“These results give confidence that an RSV vaccine for older adults is likely to provide protection against RSV infection and RSV disease, at least in the first season following vaccination,” wrote the author of an accompanying comment.

SOURCE:

The study was funded by the US Department of Veterans Affairs Cooperative Studies Program. It was published online on January 20, 2025, in The Lancet Infectious Diseases (2025 Jan 20. doi:10.1016/S1473-3099(24)00796-5)

LIMITATIONS:

This study did not account for veterans who sought care outside of the Veterans Health Administration. While the study employed rigorous matching to ensure the similarity of demographic, geographic, and clinical characteristics, there could still have been residual confounding. Also, the study was not designed to estimate the protective effect of the vaccine against mild RSV illness.

DISCLOSURES:

This study was supported by the US Department of Veterans Affairs Cooperative Studies Program and funded in part by the US Department of Health and Human Services Biomedical Advanced Research and Development Authority and US Food and Drug Administration. One of the authors reported receiving consulting support from Van-Breemen & Hynes and having a subcontract at Oregon State University for a Patient-Centered Outcomes Research Institute grant. Others reported no conflicts of interest.■

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

I would like to briefly discuss a very interesting paper that appeared in Nature:“Megastudy Shows That Reminders Boost Vaccination but Adding Free Rides Does Not.” 

Obviously, the paper has a provocative title. This is really an excellent example of what one might call implementation research, or quite frankly, what might work and what might not work in terms of having a very pragmatic goal. In this case, it was how do we get people to receive vaccinations. 

This specific study looked at individuals who were scheduled to receive or were candidates to receive COVID-19 booster vaccinations. The question came up: If you gave them free rides to the location — this is obviously a high-risk population — would that increase the vaccination rate vs the other item that they were looking at here, which was potentially texting them to remind them?

The study very importantly and relevantly demonstrated, quite nicely, that offering free rides did not make a difference, but sending texts to remind them increased the 30-day vaccination rate in this population by 21%. 

Again, it was a very pragmatic question that the trial addressed, and one might use this information in the future to increase the vaccination rate of a population where it is critical to do so. This type of research, which involves looking at very pragmatic questions and answering what is the optimal and most cost-effective way of doing it, should be encouraged. 

I encourage you to look at this paper if you’re interested in this topic.

Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, has disclosed ties with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

I would like to briefly discuss a very interesting paper that appeared in Nature:“Megastudy Shows That Reminders Boost Vaccination but Adding Free Rides Does Not.” 

Obviously, the paper has a provocative title. This is really an excellent example of what one might call implementation research, or quite frankly, what might work and what might not work in terms of having a very pragmatic goal. In this case, it was how do we get people to receive vaccinations. 

This specific study looked at individuals who were scheduled to receive or were candidates to receive COVID-19 booster vaccinations. The question came up: If you gave them free rides to the location — this is obviously a high-risk population — would that increase the vaccination rate vs the other item that they were looking at here, which was potentially texting them to remind them?

The study very importantly and relevantly demonstrated, quite nicely, that offering free rides did not make a difference, but sending texts to remind them increased the 30-day vaccination rate in this population by 21%. 

Again, it was a very pragmatic question that the trial addressed, and one might use this information in the future to increase the vaccination rate of a population where it is critical to do so. This type of research, which involves looking at very pragmatic questions and answering what is the optimal and most cost-effective way of doing it, should be encouraged. 

I encourage you to look at this paper if you’re interested in this topic.

Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, has disclosed ties with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

I would like to briefly discuss a very interesting paper that appeared in Nature:“Megastudy Shows That Reminders Boost Vaccination but Adding Free Rides Does Not.” 

Obviously, the paper has a provocative title. This is really an excellent example of what one might call implementation research, or quite frankly, what might work and what might not work in terms of having a very pragmatic goal. In this case, it was how do we get people to receive vaccinations. 

This specific study looked at individuals who were scheduled to receive or were candidates to receive COVID-19 booster vaccinations. The question came up: If you gave them free rides to the location — this is obviously a high-risk population — would that increase the vaccination rate vs the other item that they were looking at here, which was potentially texting them to remind them?

The study very importantly and relevantly demonstrated, quite nicely, that offering free rides did not make a difference, but sending texts to remind them increased the 30-day vaccination rate in this population by 21%. 

Again, it was a very pragmatic question that the trial addressed, and one might use this information in the future to increase the vaccination rate of a population where it is critical to do so. This type of research, which involves looking at very pragmatic questions and answering what is the optimal and most cost-effective way of doing it, should be encouraged. 

I encourage you to look at this paper if you’re interested in this topic.

Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, has disclosed ties with GlaxoSmithKline and AstraZeneca.

A version of this article first appeared on Medscape.com.

Almost 70 years after the discovery of the respiratory syncytial virus (RSV), vaccines and preventive treatments are giving babies a chance to beat the potentially deadly childhood infection.

As doctors turn to monoclonal antibody therapies and governments plan vaccination programs, clinical researchers are asking whether these measures will reduce the spread of the virus. Will fewer babies die from RSV, and fewer children develop permanent wheezing?

Recent studies offer clues.

Fabio Midulla, an associate professor of pediatrics at Sapienza University of Rome in Rome, Italy, said that the pharmaceutical industry is poised to push governments to use vaccines and monoclonal antibodies for even more children. “Such a push might work,” he said at the European Respiratory Society (ERS) 2024 Congress, “given that several studies have already demonstrated that their use can improve outcomes for children who do become infected and reduce societal costs by reducing hospitalizations.”

But Mariëlle WH Pijnenburg, a pulmonary specialist at Erasmus University Rotterdam in the Netherlands, said at the Congress that greater rollout would require governments to force industry to lower prices. If treatments remain beyond the reach of lower-income countries — where the burden of RSV is the greatest — the death toll from this common childhood infection will remain stubbornly high, and the prospect of global elimination will remain forever out of reach, she said.

New Tools in the Fight Against RSV

Nirsevimab, a long-acting monoclonal antibody given to newborns to prevent severe infection, was approved by the European Medicines Agency (EMA) in October 2022 and the US Food and Drug Administration (FDA) in July 2023. And Abrysvo, a vaccine given to older adults and pregnant women to stop them from passing the virus to babies from birth through 6 months of age, was approved by the FDA and the EMA in 2023.

RSV is responsible for over 33 million lung infections in children younger than 5 years annually, with more than 4 million hospitalizations and nearly 200,000 deaths. According to the Centers for Disease Control and Prevention, every year, 2.1 million children younger than 5 years old visit a healthcare provider because of an RSV infection and between 58,000 and 80,000 children younger than 5 years old are hospitalized in the United States. The burden of severe RSV disease is also high among adults, with an estimated 123,000-193,000 hospitalizations, 24,400-34,900 ICU admissions, and 4680-8620 in-hospital deaths occurring annually among US adults.

While the virus affects all age groups, it is particularly severe in infants, swelling their airways and causing them to struggle for breath. Infection in infancy can lead to later complications, such as the development of wheezing, a condition that causes breathlessness and a feeling of tightening in the chest, and possibly also asthma.

Studies have shown that children and preterm infants infected with RSV who were given monoclonal antibodies experienced less post-infection wheezing, suggesting that RSV prophylaxis could prevent the development of wheezing bronchitis.

A study conducted in Galicia, Spain, showed that only 0.3% of infants who received prophylaxis with Nirsevimab were hospitalized for RSV-related lower respiratory tract infections. “This is very promising,” Yvonne Maldonado, MD, professor of pediatrics and epidemiology and population health at Stanford University in Stanford, California, told Medscape Medical News. “But this virus is ubiquitous. It’s found everywhere. It comes around every winter season. And immunity is not long-lasting.”

Older children who are not receiving monoclonal antibodies still experience RSV-related hospitalizations, suggesting the virus continues to circulate at high enough levels in the community. “The vaccine and monoclonal antibodies can reduce the risk of hospitalization and more severe disease in young kids, but they won’t eliminate the virus,” Maldonado said. “Right now, the goal is to prevent serious infection, not to prevent the spread of the virus completely.”

Expanding Access to RSV Prevention in Low-Income Countries

Currently, the RSV vaccine and monoclonal antibodies are only given in the United States, Europe, United Kingdom, and Canada to newborns, children at risk for severe disease, and pregnant women. However, Midulla said that pharmaceutical companies are pushing to broaden the rollout to a broader population within these countries. Yet, he said, over 99% of RSV infection–related deaths occur in the Global South.

No pharmaceutical company has sought approval in low-income countries such as those in Africa. “Unless they see there being a market in a country, they’re not going to go through the onerous process of getting [a vaccine] licensed,” Shabir Madhi, dean of the faculty of health sciences and a professor of vaccinology at the University of the Witwatersrand, Johannesburg, South Africa, told Medscape Medical News.

He highlighted that almost 50% of RSV-related deaths occur in African children younger than 5 years, despite these children comprising just one fifth of the global under-5 population. The high burden of RSV mortality in the Global South is mainly due to poor access to healthcare and supportive treatments, such as supplemental oxygen, which can help children recover from severe RSV infection.

Companies are unlikely to pursue regulatory approval and licensing in low- and middle-income countries until GAVI, the global vaccine alliance, commits to procuring and funding the vaccines for these regions. GAVI’s decision would provide the necessary market incentive for manufacturers to seek approval.

Madhi suggested that GAVI’s decision on RSV vaccine procurement is imminent, likely early next year, following the World Health Organization’s Strategic Advisory Group of Experts on Immunization recommendation to vaccinate all pregnant women with the RSV vaccine, regardless of whether they are in high-income or low-income countries.

Nevertheless, even if vaccines become available, many African countries may still struggle to afford them. Madhi said that these countries would likely depend on GAVI and organizations like UNICEF to procure the vaccines at affordable prices. “The unfortunate reality is that many countries — especially in Africa — still wouldn’t be able to afford it, even if the vaccine cost as little as $5,” said Madhi. “But that’s where they would have the greatest impact.”

Midulla, Pijnenburg reported no relevant financial relationships. Madhi’s research unit, the Vaccines and Infectious Disease Analytics Unit, was involved in the clinical trials for the Pfizer RSV vaccine, the GSK RSV vaccine (which was terminated), as well as the MEDLEY trial of palivizumab. All funding for these studies went to his institution, the University of the Witwatersrand. Maldonado was Stanford principal investigator for the Pfizer RSV vaccine.
 

A version of this article appeared on Medscape.com.

Almost 70 years after the discovery of the respiratory syncytial virus (RSV), vaccines and preventive treatments are giving babies a chance to beat the potentially deadly childhood infection.

As doctors turn to monoclonal antibody therapies and governments plan vaccination programs, clinical researchers are asking whether these measures will reduce the spread of the virus. Will fewer babies die from RSV, and fewer children develop permanent wheezing?

Recent studies offer clues.

Fabio Midulla, an associate professor of pediatrics at Sapienza University of Rome in Rome, Italy, said that the pharmaceutical industry is poised to push governments to use vaccines and monoclonal antibodies for even more children. “Such a push might work,” he said at the European Respiratory Society (ERS) 2024 Congress, “given that several studies have already demonstrated that their use can improve outcomes for children who do become infected and reduce societal costs by reducing hospitalizations.”

But Mariëlle WH Pijnenburg, a pulmonary specialist at Erasmus University Rotterdam in the Netherlands, said at the Congress that greater rollout would require governments to force industry to lower prices. If treatments remain beyond the reach of lower-income countries — where the burden of RSV is the greatest — the death toll from this common childhood infection will remain stubbornly high, and the prospect of global elimination will remain forever out of reach, she said.

New Tools in the Fight Against RSV

Nirsevimab, a long-acting monoclonal antibody given to newborns to prevent severe infection, was approved by the European Medicines Agency (EMA) in October 2022 and the US Food and Drug Administration (FDA) in July 2023. And Abrysvo, a vaccine given to older adults and pregnant women to stop them from passing the virus to babies from birth through 6 months of age, was approved by the FDA and the EMA in 2023.

RSV is responsible for over 33 million lung infections in children younger than 5 years annually, with more than 4 million hospitalizations and nearly 200,000 deaths. According to the Centers for Disease Control and Prevention, every year, 2.1 million children younger than 5 years old visit a healthcare provider because of an RSV infection and between 58,000 and 80,000 children younger than 5 years old are hospitalized in the United States. The burden of severe RSV disease is also high among adults, with an estimated 123,000-193,000 hospitalizations, 24,400-34,900 ICU admissions, and 4680-8620 in-hospital deaths occurring annually among US adults.

While the virus affects all age groups, it is particularly severe in infants, swelling their airways and causing them to struggle for breath. Infection in infancy can lead to later complications, such as the development of wheezing, a condition that causes breathlessness and a feeling of tightening in the chest, and possibly also asthma.

Studies have shown that children and preterm infants infected with RSV who were given monoclonal antibodies experienced less post-infection wheezing, suggesting that RSV prophylaxis could prevent the development of wheezing bronchitis.

A study conducted in Galicia, Spain, showed that only 0.3% of infants who received prophylaxis with Nirsevimab were hospitalized for RSV-related lower respiratory tract infections. “This is very promising,” Yvonne Maldonado, MD, professor of pediatrics and epidemiology and population health at Stanford University in Stanford, California, told Medscape Medical News. “But this virus is ubiquitous. It’s found everywhere. It comes around every winter season. And immunity is not long-lasting.”

Older children who are not receiving monoclonal antibodies still experience RSV-related hospitalizations, suggesting the virus continues to circulate at high enough levels in the community. “The vaccine and monoclonal antibodies can reduce the risk of hospitalization and more severe disease in young kids, but they won’t eliminate the virus,” Maldonado said. “Right now, the goal is to prevent serious infection, not to prevent the spread of the virus completely.”

Expanding Access to RSV Prevention in Low-Income Countries

Currently, the RSV vaccine and monoclonal antibodies are only given in the United States, Europe, United Kingdom, and Canada to newborns, children at risk for severe disease, and pregnant women. However, Midulla said that pharmaceutical companies are pushing to broaden the rollout to a broader population within these countries. Yet, he said, over 99% of RSV infection–related deaths occur in the Global South.

No pharmaceutical company has sought approval in low-income countries such as those in Africa. “Unless they see there being a market in a country, they’re not going to go through the onerous process of getting [a vaccine] licensed,” Shabir Madhi, dean of the faculty of health sciences and a professor of vaccinology at the University of the Witwatersrand, Johannesburg, South Africa, told Medscape Medical News.

He highlighted that almost 50% of RSV-related deaths occur in African children younger than 5 years, despite these children comprising just one fifth of the global under-5 population. The high burden of RSV mortality in the Global South is mainly due to poor access to healthcare and supportive treatments, such as supplemental oxygen, which can help children recover from severe RSV infection.

Companies are unlikely to pursue regulatory approval and licensing in low- and middle-income countries until GAVI, the global vaccine alliance, commits to procuring and funding the vaccines for these regions. GAVI’s decision would provide the necessary market incentive for manufacturers to seek approval.

Madhi suggested that GAVI’s decision on RSV vaccine procurement is imminent, likely early next year, following the World Health Organization’s Strategic Advisory Group of Experts on Immunization recommendation to vaccinate all pregnant women with the RSV vaccine, regardless of whether they are in high-income or low-income countries.

Nevertheless, even if vaccines become available, many African countries may still struggle to afford them. Madhi said that these countries would likely depend on GAVI and organizations like UNICEF to procure the vaccines at affordable prices. “The unfortunate reality is that many countries — especially in Africa — still wouldn’t be able to afford it, even if the vaccine cost as little as $5,” said Madhi. “But that’s where they would have the greatest impact.”

Midulla, Pijnenburg reported no relevant financial relationships. Madhi’s research unit, the Vaccines and Infectious Disease Analytics Unit, was involved in the clinical trials for the Pfizer RSV vaccine, the GSK RSV vaccine (which was terminated), as well as the MEDLEY trial of palivizumab. All funding for these studies went to his institution, the University of the Witwatersrand. Maldonado was Stanford principal investigator for the Pfizer RSV vaccine.
 

A version of this article appeared on Medscape.com.

Almost 70 years after the discovery of the respiratory syncytial virus (RSV), vaccines and preventive treatments are giving babies a chance to beat the potentially deadly childhood infection.

As doctors turn to monoclonal antibody therapies and governments plan vaccination programs, clinical researchers are asking whether these measures will reduce the spread of the virus. Will fewer babies die from RSV, and fewer children develop permanent wheezing?

Recent studies offer clues.

Fabio Midulla, an associate professor of pediatrics at Sapienza University of Rome in Rome, Italy, said that the pharmaceutical industry is poised to push governments to use vaccines and monoclonal antibodies for even more children. “Such a push might work,” he said at the European Respiratory Society (ERS) 2024 Congress, “given that several studies have already demonstrated that their use can improve outcomes for children who do become infected and reduce societal costs by reducing hospitalizations.”

But Mariëlle WH Pijnenburg, a pulmonary specialist at Erasmus University Rotterdam in the Netherlands, said at the Congress that greater rollout would require governments to force industry to lower prices. If treatments remain beyond the reach of lower-income countries — where the burden of RSV is the greatest — the death toll from this common childhood infection will remain stubbornly high, and the prospect of global elimination will remain forever out of reach, she said.

New Tools in the Fight Against RSV

Nirsevimab, a long-acting monoclonal antibody given to newborns to prevent severe infection, was approved by the European Medicines Agency (EMA) in October 2022 and the US Food and Drug Administration (FDA) in July 2023. And Abrysvo, a vaccine given to older adults and pregnant women to stop them from passing the virus to babies from birth through 6 months of age, was approved by the FDA and the EMA in 2023.

RSV is responsible for over 33 million lung infections in children younger than 5 years annually, with more than 4 million hospitalizations and nearly 200,000 deaths. According to the Centers for Disease Control and Prevention, every year, 2.1 million children younger than 5 years old visit a healthcare provider because of an RSV infection and between 58,000 and 80,000 children younger than 5 years old are hospitalized in the United States. The burden of severe RSV disease is also high among adults, with an estimated 123,000-193,000 hospitalizations, 24,400-34,900 ICU admissions, and 4680-8620 in-hospital deaths occurring annually among US adults.

While the virus affects all age groups, it is particularly severe in infants, swelling their airways and causing them to struggle for breath. Infection in infancy can lead to later complications, such as the development of wheezing, a condition that causes breathlessness and a feeling of tightening in the chest, and possibly also asthma.

Studies have shown that children and preterm infants infected with RSV who were given monoclonal antibodies experienced less post-infection wheezing, suggesting that RSV prophylaxis could prevent the development of wheezing bronchitis.

A study conducted in Galicia, Spain, showed that only 0.3% of infants who received prophylaxis with Nirsevimab were hospitalized for RSV-related lower respiratory tract infections. “This is very promising,” Yvonne Maldonado, MD, professor of pediatrics and epidemiology and population health at Stanford University in Stanford, California, told Medscape Medical News. “But this virus is ubiquitous. It’s found everywhere. It comes around every winter season. And immunity is not long-lasting.”

Older children who are not receiving monoclonal antibodies still experience RSV-related hospitalizations, suggesting the virus continues to circulate at high enough levels in the community. “The vaccine and monoclonal antibodies can reduce the risk of hospitalization and more severe disease in young kids, but they won’t eliminate the virus,” Maldonado said. “Right now, the goal is to prevent serious infection, not to prevent the spread of the virus completely.”

Expanding Access to RSV Prevention in Low-Income Countries

Currently, the RSV vaccine and monoclonal antibodies are only given in the United States, Europe, United Kingdom, and Canada to newborns, children at risk for severe disease, and pregnant women. However, Midulla said that pharmaceutical companies are pushing to broaden the rollout to a broader population within these countries. Yet, he said, over 99% of RSV infection–related deaths occur in the Global South.

No pharmaceutical company has sought approval in low-income countries such as those in Africa. “Unless they see there being a market in a country, they’re not going to go through the onerous process of getting [a vaccine] licensed,” Shabir Madhi, dean of the faculty of health sciences and a professor of vaccinology at the University of the Witwatersrand, Johannesburg, South Africa, told Medscape Medical News.

He highlighted that almost 50% of RSV-related deaths occur in African children younger than 5 years, despite these children comprising just one fifth of the global under-5 population. The high burden of RSV mortality in the Global South is mainly due to poor access to healthcare and supportive treatments, such as supplemental oxygen, which can help children recover from severe RSV infection.

Companies are unlikely to pursue regulatory approval and licensing in low- and middle-income countries until GAVI, the global vaccine alliance, commits to procuring and funding the vaccines for these regions. GAVI’s decision would provide the necessary market incentive for manufacturers to seek approval.

Madhi suggested that GAVI’s decision on RSV vaccine procurement is imminent, likely early next year, following the World Health Organization’s Strategic Advisory Group of Experts on Immunization recommendation to vaccinate all pregnant women with the RSV vaccine, regardless of whether they are in high-income or low-income countries.

Nevertheless, even if vaccines become available, many African countries may still struggle to afford them. Madhi said that these countries would likely depend on GAVI and organizations like UNICEF to procure the vaccines at affordable prices. “The unfortunate reality is that many countries — especially in Africa — still wouldn’t be able to afford it, even if the vaccine cost as little as $5,” said Madhi. “But that’s where they would have the greatest impact.”

Midulla, Pijnenburg reported no relevant financial relationships. Madhi’s research unit, the Vaccines and Infectious Disease Analytics Unit, was involved in the clinical trials for the Pfizer RSV vaccine, the GSK RSV vaccine (which was terminated), as well as the MEDLEY trial of palivizumab. All funding for these studies went to his institution, the University of the Witwatersrand. Maldonado was Stanford principal investigator for the Pfizer RSV vaccine.
 

A version of this article appeared on Medscape.com.