About
The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.
Summary
Question: Should all previously hepatitis B (HepB)-unvaccinated adults receive HepB vaccination?
Population: Previously HepB-unvaccinated adults age ≥ 18 years
Intervention: Universal HepB vaccination strategy (2- and 3-dose schedules)
Comparison(s): Current risk based recommendation
Outcomes:
- Incidence of hepatitis B
- Morbidity related to hepatitis B
- Mortality related to hepatitis B
- Serious adverse events associated with the 2-dose vaccine*
*This outcome was solely aimed at assessing the 2-dose HepB-CpG (Heplisav-B, FDA-approved in 2017). The 3-dose, single-antigen HepB vaccines had already been evaluated for their adverse events profiles and had undergone post-licensure assessment.
Background
Since hepatitis B (HepB) vaccine introduction in 1982, there have been substantial declines in reported hepatitis B cases. However, despite reductions in hepatitis B incidence achieved through incremental HepB vaccine policy over the past four decades, from a high of 26,654 reported cases (172,700 estimated) in 1985 to a low of 2,791 reported cases (18,100 estimated) in 2014, progress has stalled in further reducing hepatitis B incidence.1 In 2018, the reported HepB vaccination coverage (≥3 doses) was overall 30.0% for adults ≥19 years old, demonstrating small increases in coverage throughout the past four decades,2 including low coverage among persons in recommended risk groups (e.g., 33% coverage among persons with chronic liver disease).
Acute cases have been rising over the past decade among persons age >40 years, particularly among persons aged 40-49 years (2.7 reported cases per 100,000 population), and persons aged 50-59 years (1.6 reported cases per 100,000 population). This is consistent with low coverage among disproportionately affected populations in this age group (e.g., persons who inject drugs, persons at risk of sexual transmission). In 1991, all U.S. infants were recommended for HepB vaccination.3 In 1999, all US children and adolescents through age 18 years who have not received Hep B vaccine were added to the HepB recommendations.3
Problem
Criteria | Work Group Judgements | Evidence | Additional Information |
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Is the problem of public health importance? | Yes | The burden of chronic hepatitis B virus (HBV) disease in the US remains substantial.1-4
Limited availability of information regarding risk behaviors or exposures associated with reported cases of acute HBV infection — US, 20194
Chronic HBV infection develops in5:
Chronic HBV infection leads to 15-25% risk for premature death from cirrhosis or liver cancer6 Missed opportunities in HepB vaccination coverage among adults ≥19 years7
Age, % vaccinated, (95% CI) with 1+ risk factors reported8:
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HHS Target Measure: Reduce acute HBV infections 90% by 203011 |
Benefits and Harms
Criteria | Work Group Judgements | Evidence | Additional Information |
---|---|---|---|
How substantial are the desirable anticipated effects? | Large | Seroprotection
Vaccine effectiveness
Outcomes averted over cohort lifetime7* Number averted (% additional averted): Acute HBV infections
428,485 (24.8%)
Chronic HBV infections
34,200 (24.2%)
Hepatitis B-related deaths
78,808 (22.8%)
Hepatocellular carcinoma
59,477 (28.8%)
*Assumes a 3-dose strategy base case, averting additional hepatitis B-related outcomes compared with baseline current risk-based strategy. Analytic horizon is the lifetime of the cohort, (on average, ~35 years per person).
Vaccinate general population before chronic liver disease (CLD) and other comorbidities (e.g., obesity, diabetes) develop. Patients with CLD are known to have decreased immunogenicity with the conventional (3-dose) vaccine8, 9.
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How substantial are the undesirable anticipated effects? | Minimal | Rare side effects/adverse reactions1,2
HepB-CpG vaccine (Heplisav-B): minimal mild and severe adverse events (see the accompanying GRADE tables) Pregnancy
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Heplisav-B Pregnancy Registry:
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Do the desirable effects outweigh the undesirable effects? | Favors intervention |
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What is the overall certainty of this evidence for the critical outcomes? | Effectiveness of the intervention: No studies found Safety of the intervention:
Moderate |
No published empirical evidence was available on coverage among risk groups following a change to a universal or age-based HepB adult recommendation.
Regarding safety, please refer to GRADE evidence profiles for detailed assessment of the certainty of the evidence.
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Values
Criteria | Work Group Judgements | Evidence | Additional Information |
---|---|---|---|
Does the target population feel that the desirable effects are large relative to undesirable effects? | Probably yes | Values and preferences vary by risk status/group
Work Group felt that “All other persons seeking protection from HBV infection” is an insufficient recommendation. Puts the burden on the patient to request vaccination, and a universal recommendation might empower the provider to proactively offer vaccine. |
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Is there important uncertainty about or variability in how much people value the main outcomes? | Probably not important uncertainty or variability | Limited information on persons with lower risks
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Acceptability
Criteria | Work Group Judgements | Evidence | Additional Information |
---|---|---|---|
Is the intervention acceptable to key stakeholders? | Probably yes Yes (Work Group split between probably yes/ yes)
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Stakeholder support for universal adult HepB vaccine recommendation and improving adult immunization rates1-5
A national provider survey assessed adult HepB vaccination practices among 433 family medicine physicians and 420 internists in the US6
Physicians report that the main barriers to stocking and administering adult HepB vaccines were financial
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A national provider survey demonstrated that patient and provider concerns about vaccine SAFETY were not substantial barriers to vaccinate.6 |
Resource Use
Criteria | Work Group Judgements | Evidence | Additional Information |
---|---|---|---|
Is the intervention a reasonable and efficient allocation of resources? | Yes | A cost utility analysis compared current vaccination recommendations with either 3-dose or 2-dose universal HepB vaccination (intervention strategies). Results were similar for both the 3-dose and 2-dose strategies. In both strategies, universal HepB vaccination improved health and increased costs. For brevity, results from the 3-dose strategy are summarized in the subsequent paragraph, followed by a summary of a 2-dose strategy:
The analysis found universal adult HepB vaccination increased protected persons by 21%, reduced acute HBV infections by 24%, reduced HepB-related deaths by 23% and cost $153,000 per QALY gained with NNV to avert an acute infection equal to 372. When additional high-risk individuals were vaccinated, the expected cost per QALY gained decreased to $137,000 and NNV decreased to 334.
2-dose strategy summary
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In the base case, the model conservatively assumed that no additional high-risk individuals would be vaccinated following the intervention. When this assumption was relaxed, allowing 20% additional vaccinations to occur in high-risk groups, the cost per QALY and the NNV to avert a case both declined.
In an age-based analysis, the estimated costs per QALY increased at older ages, primarily due to lower incidence levels at older ages.
Limitations
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Equity
Criteria | Work Group Judgements | Evidence | Additional Information |
---|---|---|---|
What would be the impact on health equity? | Increased | Racial disparity in HBV infection rates showed slow improvement
Risk factors assessed include socio-structural factors that may criminalize and stigmatize5 A universal vaccination recommendation could eliminate the need for risk factor assessment prior to vaccination and reduce stigma among people who have been marginalized and who are at increased risk, and immigrants with concerns about stigma associated with hepatitis B-related care.9, 10,11 |
¶ p<0.05 by t–test for comparisons with white as the reference.
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Feasibility
Criteria | Work Group Judgements | Evidence | Additional Information |
---|---|---|---|
Is the intervention feasible to implement? | Yes | Adding universal HepB recommendation to the recommended adult schedule can be implemented with the existing adult vaccine infrastructure.
The universal HepB recommendation will be simpler to implement than the current risk-based strategy.
Implementation will require integration with CDC hepatitis B screening/testing guidelines, which are concurrently being updated by a parallel CDC process.
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Balance of consequences
Desirable consequences clearly outweigh undesirable consequences in most settings.
Is there sufficient information to move forward with a recommendation? Yes.
Final deliberation and decision by the ACIP
Final ACIP recommendation
ACIP recommends the intervention.
Conclusion
Based on the Evidence to Recommendation Framework, the ACIP voted on November 3, 2021 as follows:
The following groups should receive HepB vaccine:
- Adults aged 19 through 59 years
- Adults aged 60 years and older with risk factors for hepatitis B
The following group may receive HepB vaccines:
- Adults aged 60 years and older without known risk factors for hepatitis B
References
Background:
- 2019 Viral Hepatitis Surveillance Report. 2021, Centers for Disease Control and Prevention.
- Lu, P.J., et al., Surveillance of Vaccination Coverage Among Adult Populations -United States, 2018. MMWR Surveill Summ, 2021. 70(3): p. 1-26.
- National Notifiable Diseases Surveillance System (NNDSS). www.cdc.gov/nndss/index.html.
Problem:
- Roberts, H., D. Kruszon-Moran, K. N. Ly, E. Hughes, K. Iqbal, R. B. Jiles and S. D. Holmberg (2016). "Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2012." Hepatology 63(2): 388-397.
- Lim, J. K., M. H. Nguyen, W. R. Kim, R. Gish, P. Perumalswami and I. M. Jacobson (2020). "Prevalence of Chronic Hepatitis B Virus Infection in the United States." Official journal of the American College of Gastroenterology | ACG 115(9): 1429-1438.
- Wong RJ, Brosgart CL, Welch S, Block T, Chen M, Cohen C, Kim WR, Kowdley KV, Lok AS, Tsai N, Ward J, Wong SS, Gish RG. An Updated Assessment of Chronic Hepatitis B Prevalence Among Foreign-Born Persons Living in the United States. Hepatology. 2021 Aug;74(2):607-626. doi: 10.1002/hep.31782. Epub 2021 May 26.
- 2019 CDC Hepatitis Surveillance Report. www.cdc.gov/hepatitis/statistics/2019surveillance/HepB.htm
- Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis. 1995 Apr;20(4):992-1000. doi: 10.1093/clinids/20.4.992. PMID: 7795104.
- Hepatitis B Virus (HBV) Infection. Sexually Transmitted Infections Treatment Guidelines, 2021. www.cdc.gov/std/treatment-guidelines/hbv.htm
- Ladak, F., A. Gjelsvik, E. Feller, S. R. Rosenthal and B. T. Montague (2012). "Hepatitis B in the United States: ongoing missed opportunities for hepatitis B vaccination, evidence from the Behavioral Risk Factor Surveillance Survey, 2007." Infection 40(4): 405-413.
- CDC unpublished, NHIS 2018.
- Hyer, R. N. and R. S. Janssen (2018). "HBSAG-1018, a two-dose hepatitis b vaccine, is well tolerated and effective in diabetic patients aged 60 years or older." Diabetes 67 (Supplement 1): LB60.
- Miller-Handley, H., G. Paulsen, D. Hooper, D. Lazear, M. Lake and L. Danziger-Isakov (2016). "Durability of the hepatitis B seroprotection in pediatric renal transplant recipients." Open Forum Infectious Diseases. Conference: ID Week 3(Supplement 1).
- Viral Hepatitis National Strategic Plan for the United States: A Roadmap to Elimination 2021-2025 (Viral Hepatitis Plan or Plan), January 7, 2021. https://www.hhs.gov/hepatitis/viral-hepatitis-national-strategic-plan/index.html
Benefits:
- Assad S, Francis A. Over a decade of experience with a yeast recombinant hepatitis B vaccine. Vaccine. 1999 Aug 20;18(1-2):57-67. doi: 10.1016/s0264-410x(99)00179-6. PMID: 10501235.
- Venters C, Graham W, Cassidy W. Recombivax-HB: perspectives past, present and future. Expert Rev Vaccines. 2004 Apr;3(2):119-29. doi: 10.1586/14760584.3.2.119. PMID: 15056038.
- André FE. Summary of safety and efficacy data on a yeast-derived hepatitis B vaccine. Am J Med. 1989 Sep 4;87(3A):14S-20S. doi: 10.1016/0002-9343(89)90525-1. PMID: 2528292.
- Schillie, S., A. Harris, R. Link-Gelles, J. Romero, J. Ward and N. Nelson (2018). "Recommendations of the Advisory Committee on Immunization Practices for Use of a Hepatitis B Vaccine with a Novel Adjuvant." MMWR – Morbidity & Mortality Weekly Report 67(15): 455-458.
- Bruce, M. G., D. Bruden, D. Hurlburt, C. Zanis, G. Thompson, L. Rea, M. Toomey, L. Townshend-Bulson, K. Rudolph, L. Bulkow, P. R. Spradling, R. Baum, T. Hennessy and B. J. McMahon (2016). "Antibody Levels and Protection After Hepatitis B Vaccine: Results of a 30-Year Follow-up Study and Response to a Booster Dose." Journal of Infectious Diseases 214(1): 16-22.
- Nelson, N. P., P. J. Easterbrook and B. J. McMahon (2016). "Epidemiology of Hepatitis B Virus Infection and Impact of Vaccination on Disease." Clinics in Liver Disease 20(4): 607-628.
- Hall, Eric. "Economic Evaluation of Universal Hepatitis B Vaccination Among Adults." Presented to ACIP February 23, 2021.
- Roni, D.A., et al., Safety and Efficacy of Hepatitis B Vaccination in Cirrhosis of Liver. Advances in Virology, 2013. 2013: p. 196704.
- Moreno-Fernandez, J., J. A. Garcia-Seco, E. M. O. Rodrigo, A. M. S. Segura, F. Garcia-Seco and J. R. Munoz-Rodriguez (2020). "Vaccination adherence to influenza, pneumococcal and hepatitis B virus in adult type 1 diabetes mellitus patients." Primary care diabetes 14(4): 343-348.
Harms:
- Assad S, Francis A. Over a decade of experience with a yeast recombinant hepatitis B vaccine. Vaccine. 1999 Aug 20;18(1-2):57-67. doi: 10.1016/s0264-410x(99)00179-6. PMID: 10501235.
- Haber, P., P. L. Moro, C. Ng, P. W. Lewis, B. Hibbs, S. F. Schillie, N. P. Nelson, R. Li, B. Stewart and M. V. Cano (2018). "Safety of currently licensed hepatitis B surface antigen vaccines in the United States, Vaccine Adverse Event Reporting System (VAERS), 2005-2015." Vaccine 36(4): 559-564.
- Schillie, S., A. Harris, R. Link-Gelles, J. Romero, J. Ward and N. Nelson (2018). "Recommendations of the Advisory Committee on Immunization Practices for Use of a Hepatitis B Vaccine with a Novel Adjuvant." MMWR – Morbidity & Mortality Weekly Report 67(15): 455-458.
- McCarthy, N. L., J. Gee, L. Sukumaran, E. Weintraub, J. Duffy, E. O. Kharbanda, R. Baxter, S. Irving, J. King, M. F. Daley, R. Hechter and M. M. McNeil (2016). "Vaccination and 30-day mortality risk in children, adolescents, and young adults." Pediatrics 137 (3) (no pagination)(e20152970).
- Groom, H. C., S. A. Irving, P. Koppolu, N. Smith, G. Vazquez-Benitez, E. O. Kharbanda, M. F. Daley, J. G. Donahue, D. Getahun, L. A. Jackson, A. Tse Kawai, N. P. Klein, N. L. McCarthy, J. D. Nordin, L. Sukumaran and A. L. Naleway (2018). "Uptake and safety of Hepatitis B vaccination during pregnancy: A Vaccine Safety Datalink study." Vaccine 36(41): 6111-6116.
Values:
- Bridges, C. B., T. L. Watson, N. P. Nelson, M. Chavez-Torres, P. Fineis, B. Ntiri-Reid, E. Wake, J. M. Leahy, A. K. Kurian, M. A. K. Hall and E. D. Kennedy (2019). "Challenges with hepatitis B vaccination of high risk adults – A pilot program." Vaccine 37(35): 5111-5120.
- Owiti, J. A., T. Greenhalgh, L. Sweeney, G. R. Foster and K. S. Bhui (2015). "Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review." BMC Public Health 15(1): 151.
- Ma, G. X., C. Y. Fang, S. E. Shive, J. Toubbeh, Y. Tan and P. Siu (2007). "Risk perceptions and barriers to Hepatitis B screening and vaccination among Vietnamese immigrants." Journal of Immigrant & Minority Health 9(3): 213-220.
Acceptability:
- Schiff, E. R., B. A. Connor, J. H. Hershey, M. C. Mahoney and W. Schaffner (2007). "Recommendations from a national conference on universal vaccination against hepatitis B and hepatitis A in adults." Journal of Applied Research 7(1): 3-16.
- Schaffner, William. Time for a bold advance to defeat hepatitis B | The Hill. The Hill, 2021 April 30. https://thehill.com/opinion/healthcare/551192-time-for-a-bold-advance-to-defeat-hepatitis-b
- "Stakeholder Roundtable: Improving Adult Immunization Rates." America's Health Insurance Plans. August 2015. https://www.ahip.org/wp-content/uploads/2016/04/Vaccine_Report_8.26.15-1.pdf
- Harris, A. M., K. Iqbal, S. Schillie, J. Britton, M. A. Kainer, S. Tressler and C. Vellozzi (2016). "Increases in Acute Hepatitis B Virus Infections – Kentucky, Tennessee, and West Virginia, 2006-2013." MMWR – Morbidity & Mortality Weekly Report 65(3): 47-50.
- America's Health Insurance Plan Report (2015): https://www.nfid.org/wp-content/uploads/2019/08/cta-hep-b-at-risk-adults.pdf
- Daley, M. F., K. A. Hennessey, C. M. Weinbaum, S. Stokley, L. P. Hurley, L. A. Crane, B. L. Beaty, J. C. Barrow, C. I. Babbel, L. M. Dickinson and A. Kempe (2009). "Physician practices regarding adult hepatitis B vaccination: a national survey." Am J Prev Med 36(6): 491-496.
- Hurley, L. P., C. B. Bridges, R. Harpaz, M. A. Allison, S. T. O'Leary, L. A. Crane, M. Brtnikova, S. Stokley, B. L. Beaty, A. Jimenez-Zambrano, F. Ahmed, C. Hales and A. Kempe (2014). "U.S. physicians' perspective of adult vaccine delivery." Annals of Internal Medicine 160(3): 161-170.
- Equils, O., C. Kellogg, L. Baden, W. Berger and S. Connolly (2019). "Logistical and structural challenges are the major obstacles for family medicine physicians' ability to administer adult vaccines." Human Vaccines and Immunotherapeutics 15(3): 637-642.
Resource use:
- Hall, Eric. "Economic Evaluation of Universal Hepatitis B Vaccination Among Adults." Presented to ACIP February 23, 2021.
Equity:
- Wasley, A., S. Grytdal and K. Gallagher (2008). "Surveillance for acute viral hepatitis — United States, 2006...MMWR SURVEILLANCE SUMMMMWR: Surveillance Summaries." MMWR Surveillance Summaries 57(SS-2): 1-24.
- Harris, A. M., K. Iqbal, S. Schillie, J. Britton, M. A. Kainer, S. Tressler and C. Vellozzi (2016). "Increases in Acute Hepatitis B Virus Infections – Kentucky, Tennessee, and West Virginia, 2006-2013." MMWR – Morbidity & Mortality Weekly Report 65(3): 47-50.
- 2019 CDC Hepatitis Surveillance Report. www.cdc.gov/hepatitis/statistics/2019surveillance/HepB.htm
- Schiff, E. R., B. A. Connor, J. H. Hershey, M. C. Mahoney and W. Schaffner (2007). "Recommendations from a national conference on universal vaccination against hepatitis B and hepatitis A in adults." Journal of Applied Research 7(1): 3-16.
- Taylor, J. E. B., J. Surey, J. MacLellan, M. Francis, I. Abubakar and H. R. Stagg (2019). "Hepatitis B vaccination uptake in hard-to-reach populations in London: a cross-sectional study." BMC Infectious Diseases 19(1): 372.
- Figgatt, M., J. Hildick-Smith, E. Addish, J. Coleman, J. Benitez, C. Freeland, S. Alles, K. Viner, C. Johnson and D. Kuncio (2020). "Susceptibility to Hepatitis A and B Virus Among Clients at a Syringe Services Program in Philadelphia, 2018." Public Health Reports 135(5): 691-699.
- Collier, M. G., J. Drobeniuc, J. Cuevas-Mota, R. S. Garfein, S. Kamili and E. H. Teshale (2015). "Hepatitis A and B among young persons who inject drugs-Vaccination, past, and present infection." Vaccine 33(24): 2808-2812.
- Topp, L., C. Day, G. J. Dore and L. Maher (2009). "Poor criterion validity of self-reported hepatitis B infection and vaccination status among injecting drug users: A review." Drug and Alcohol Review 28(6): 669-675.
- Kim, M.-J., H. Lee, P. Kiang, P. Watanabe, M. Torres, P. Halon, L. Shi and D. Church (2015). "Debunking the myth: low knowledge levels of HBV infection among Asian American college students." Asia-Pacific Journal of Oncology Nursing 2(1): 8-16.
- Mokaya, J., A. McNaughton, L. Burbridge, T. Maponga, G. O'Hara, M. Andersson, J. Seeley and P. Matthews (2018). "A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection – A systematic review [version 2; peer review: 2 approved]." Wellcome Open Research 3(29).
- Owiti, J. A., T. Greenhalgh, L. Sweeney, G. R. Foster and K. S. Bhui (2015). "Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review." BMC Public Health 15(1): 151.
Feasibility:
- Bridges, C. B., T. L. Watson, N. P. Nelson, M. Chavez-Torres, P. Fineis, B. Ntiri-Reid, E. Wake, J. M. Leahy, A. K. Kurian, M. A. K. Hall and E. D. Kennedy (2019). "Challenges with hepatitis B vaccination of high-risk adults – A pilot program." Vaccine 37(35): 5111-5120.
- "Hepatitis B Vaccination." Report on Adult Immunizations in Texas: Behavioral Risk Factor Surveillance System 2018. Texas Department of State Health Services. https://www.dshs.texas.gov/immunize/coverage/archive/DSHS-Texas_BRFSS_Vaccine_Report_2018.pdf.
- Miller-Handley, H., G. Paulsen, D. Hooper, D. Lazear, M. Lake and L. Danziger-Isakov (2016). "Durability of the hepatitis B seroprotection in pediatric renal transplant recipients." Open Forum Infectious Diseases. Conference: ID Week 3(Supplement 1).
- Bailey, C. L., V. Smith and M. Sands (2008). "Hepatitis B vaccine: a seven-year study of adherence to the immunization guidelines and efficacy in HIV-1-positive adults." International Journal of Infectious Diseases 12(6): e77-e83.
- Schiff, E. R., B. A. Connor, J. H. Hershey, M. C. Mahoney and W. Schaffner (2007). "Recommendations from a national conference on universal vaccination against hepatitis B and hepatitis A in adults." Journal of Applied Research 7(1): 3-16.
- Hechter, R. C., L. Qian, Y. Luo, D. S. Ling Grant, R. Baxter, N. P. Klein, K. Valdez Nunley, L. Aukes, C. Hogea, G. Krishnarajah, B. J. Patterson, T. M. Im and H. F. Tseng (2019). "Impact of an electronic medical record reminder on hepatitis B vaccine initiation and completion rates among insured adults with diabetes mellitus." Vaccine 37(1): 195-201.
- Lu, P.J., et al., Surveillance of Vaccination Coverage Among Adult Populations -United States, 2018. MMWR Surveill Summ, 2021. 70(3): p. 1-26.
- Flu Vaccination Coverage, United States, 2019–20 Influenza Season: CDC. www.cdc.gov/flu/fluvaxview/coverage-1920estimates.htm
- Wu, Y., J. A. Marsh, E. S. McBryde and T. L. Snelling (2018). "The influence of incomplete case ascertainment on measures of vaccine efficacy." Vaccine 36(21): 2946-2952.
- Bruxvoort, K., J. Slezak, J. W. Hsu, K. Reynolds, L. S. Sy and S. Jacobsen (2019). "Hepatitis B vaccine and risk of acute myocardial infarction among patients with diabetes." Annals of Epidemiology 36: 71.
- Rosenthal, E. M., E. W. Hall, E. S. Rosenberg, A. Harris, N. P. Nelson and S. Schillie (2020). "Assessing the cost-utility of preferentially administering Heplisav-B vaccine to certain populations." Vaccine 38(51): 8206-8215.