Immunizations in HIV and Aging (5/18/17)

  • There is a large body of data that vaccine preventable illnesses occur with greater frequency and are more severe in people living with HIV (PLWH) than in age-matched control subjects. Thus, a number of vaccines are indicated in PLWH.

Consensus is widespread for the use of most vaccines in persons living with HIV (PLWH). These recommendations are nicely summarized in an Infectious Diseases Society of America Guideline for Vaccination of the Immunocompromised Host and are also available from the Centers for Disease Control and Prevention (CDC) [1, 2]

Current CDC Vaccine Recommendations

PLWH should be immunized according to the CDC schedule for adults, including regular primary and booster dose schedules based on age for Td/Tdap, hepatitis A and B, inactivated polio, and human papillomavirus (HPV), as well as annual influenza immunization.  In addition, PLWH should receive combination pneumococcal vaccines  (13-valent protein-conjugated pneumococcal vaccine (PCV13) should be followed by a dose of pneumococcal polysaccharide vaccine (PPSV23) at least eight weeks later with a 2nd dose 5 years later) and meningococcal conjugate vaccine regardless of age.[2]   Live-attenuated organism vaccines are generally contraindicated, but in patients with a CD4 count > 200/mm3 mumps, measles and rubella (MMR) and varicella vaccines are indicated in patients not previously immunized. Particular caution should be noted in using yellow fever vaccine for travelers with HIV infection, but immunization can be considered for those at high risk of acquiring the disease during travel if they have well-controlled HIV and CD4 counts > 200 mm3.

Efficacy and Evidence for a Change in Vaccine Responsiveness with Advancing Age in PLWH

In persons without HIV infection, vaccine responsiveness declines with age but differs by the vaccine. For example, hepatitis B vaccine responses begin to decline around age 35-40, whereas zoster and pneumococcal polysaccharide vaccine (PPSV23) responses begin waning about age 70-75 years [3]. Do vaccine responses wane at an earlier age in PLWH, and should this influence the recommended adult immunization schedule? Although data are limited, there is some suggestion that HIV does accelerate and/or enhance age-related declines in vaccine response. Two studies examined PPSV23 and pneumonia prevention in HIV-positive adults using age as a variable. Teshale et al. showed that age 45+ was associated with allcause pneumonia, even after adjustment for vaccine status, indicating advanced age was associated with poorer vaccine efficacy[4]. However, Rodriguez-Barradas et al. found no such association in the VACS cohort[5]. PPSV23 was protective when pneumonia was examined as an outcome in that study only in HIV-positive adults (average age 49 years). Efficacy of influenza vaccination in PLWH has been examined in several studies, with response dependent on CD4 count (Fig. 1).[6]

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The most extensive examination of age and vaccine response in = PLWH on ART therapy was published by Andrade et al. in a comparison of PLWH on anti-retroviral therapy (ART) < 40 (mean age 31 years)  vs. those 50 (mean age 59 years)[7]. All participants had an undetectable viral load for two years and CD4 counts > 400. An HIV-negative comparison group included young (mean age 28 years) and aged (mean age 61 years) gender-matched controls. All had been immunized with tetanus toxoid (TT) during childhood, but not since; each subject was given a single TT boost. HIV-positive adults age > 50 (Fig. 2) demonstrated significantly reduced humoral (serum IgG) and cellular (T cell interferon production) responses after TT immunization. Additional in vitro studies show anti-IL-10 improved responses in aged HIV negative patients, but not in HIV-positive aged, suggesting the mechanism of vaccine non-response differs. Since TT is a recall response, and naive responses are more severely affected by age, one would anticipate naive responses would be similarly, or more severely, reduced.

New Recommendations for Meningococcal Immunization for HIV-Infected Patients

The CDC now recommends that all PLWH aged 2 years and older should receive two doses of the meningococcal conjugate vaccine (serogroups A, C, W, and Y) separated by at least eight weeks.[8] This recommendation is based on data showing higher incidence of meningococcal infection in PLWH compared to HIV-negative persons.  Notably, in the United States, 92% of meningococcal infections in PLWH were in adults ages 20-59 years.  For PLWH 56 years and older, the meningococcal conjugate vaccine is recommended over the polysaccharide vaccine as data suggest improved immunogenicity after a booster dose of the conjugate compared to the polysaccharide vaccine.[8, 9]

Screen Shot 2017-04-27 at 10.10.54 PM

Special Considerations: dosing of the Inactivated Influenza Vaccine (IIV)

A high-dose IIV is available for individuals ≥65 years of age; FDA approval was based on data showing increased immunogenicity of the high-dose vaccine in older adults. A large randomized trial over two flu seasons to examine clinical efficacy was completed. High-dose (60 µg of protein) IIV was compared to standard dose (15 µg protein) IIV for clinical efficacy and had a relative efficacy of 24% (95% CI 9.7%-36.5%) compared with standard dose IIV. There were 227 lab-confirmed cases among the 15,892 participants who got high-dose IIV, for a rate of 1.43%, and 300 cases among the 15,911 who received the standard dose IIV, for a rate of 1.83%. This exceeded the FDA-mandated definition required for superiority (lower bound of the 95% confidence interval > 9.1%). No PLWH were knowingly included in this study, but HIV testing was not performed. At this time, however, the ACIP has not stated a preference for high-dose vaccine over the standard-dose vaccine in older adults.

In a small clinical trial of PLWH (n=190) randomized to receive high-dose vs. standard-dose IIV, immune responses were superior in the high-dose group, similar to the results noted above for seniors[10]. Now, however, there is no recommendation to use high-dose IIV in HIV subjects unless they meet the age criteria, > 65.

The timing of influenza vaccination in PLWH has also come into question. A retrospective cohort study (study period 2005-2013) reviewed the records of 1176 PLWH  and determined that people who received the influenza vaccine “early” (September 1 through November 15) were more likely to be diagnosed with influenza or an influenza-like illness (ILI) compared to people who received the vaccination “late” (after November 15).[11]  This study raises questions for further investigation, including the role for booster dosing during the influenza season for PLWH or offering PLWH influenza vaccination later in the fall.

Special Considerations: Zoster Vaccine

Presently, the herpes zoster vaccine is not recommended for PLWH since it is a live-attenuated formulation and concerns exist about harm in the setting of immune dysfunction.  A Phase I/II trial investigating the safety and immunogenicity of an alternative to the current live-attenuated version, a herpes zoster subunit vaccine, showed persistent antibody production and no adverse events at 18 months’ follow-up. [12] There are otherwise surprisingly few data on zoster vaccine in PLWH, despite substantial data on varicella vaccine.   An ongoing trial (ClinTrials.gov #NCT00851786, currently in analysis phase) may address this deficiency. 

Future Directions in Hepatitis B Vaccination

As stated above, all PLWH should be vaccinated against Hepatitis B as per the CDC guidelines.  More recent data suggest improved sustained immunogenicity with a 40 μg dose at weeks 0, 4, 8, and 24 compared to the current standard 20 μg dose at weeks 0, 4, and 24.[13]

Updated by Katherine Schafer, MD, March 2017

References

  1. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58(3):e44-100.
  2. Centers for Disease Control and Prevention. HIV infection and adult vaccination. In. https://www.cdc.gov/vaccines/schedules/easy-to-read/adult.html
  3. High KP, D’Aquila RT, Fuldner RA, Gerding DN, Halter JB, Haynes L, et al. Workshop on immunizations in older adults: identifying future research agendas. J Am Geriatr Soc 2010; 58(4):765-776.
  4. Teshale EH, Hanson D, Flannery B, Phares C, Wolfe M, Schuchat A, et al. Effectiveness of 23-valent polysaccharide pneumococcal vaccine on pneumonia in HIV-infected adults in the United States, 1998–2003. Vaccine 2008; 26(46):5830-5834.
  5. Rodriguez-Barradas MC, Goulet J, Brown S, Goetz MB, Rimland D, Simberkoff MS, et al. Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study. Clin Infect Dis 2008; 46(7):1093-1100.
  6. Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis 2009; 9(8):493-504.
  7. Andrade RM, Andrade AF, Lazaro MA, Vieira MM, Barros PO, Borner AR, et al. Failure of highly active antiretroviral therapy in reconstituting immune response to Clostridium tetani vaccine in aged AIDS patients. J Acquir Immune Defic Syndr 2010; 54(1):10-17.
  8. MacNeil JR, Rubin LG, Patton M, Ortega-Sanchez IR, Martin SW. Recommendations for Use of Meningococcal Conjugate Vaccines in HIV-Infected Persons – Advisory Committee on Immunization Practices, 2016. MMWR Morb Mortal Wkly Rep 2016; 65(43):1189-1194.
  9. Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013; 62(RR-2):1-28.
  10. McKittrick N, Frank I, Jacobson JM, White CJ, Kim D, Kappes R, et al. Improved immunogenicity with high-dose seasonal influenza vaccine in HIV-infected persons: a single-center, parallel, randomized trial. Ann Intern Med 2013; 158(1):19-26.
  11. Glinka ER, Smith DM, Johns ST. Timing Matters – Influenza Vaccination to HIV-Infected Patients. HIV Med 2016; 17(8):601-604.
  12. Berkowitz EM, Moyle G, Stellbrink HJ, Schurmann D, Kegg S, Stoll M, et al. Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study. J Infect Dis 2015; 211(8):1279-1287.
  13. Launay O, Rosenberg AR, Rey D, Pouget N, Michel ML, Reynes J, et al. Long-term Immune Response to Hepatitis B Virus Vaccination Regimens in Adults With Human Immunodeficiency Virus 1: Secondary Analysis of a Randomized Clinical Trial. JAMA Intern Med 2016; 176(5):603-610.
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