Update on Vaccination Recommendations for Adults with HIV

Abstract

Purpose of Review

Vaccination recommendations for people with HIV (PWH) differ from the general population given potential for diminished immune responses as well as increased risk for infection or more severe disease. This review highlights updated vaccine recommendations, summarizes available data informing use of vaccines, and identifies areas in need of additional study for adults with HIV.

Recent Findings

Vaccine recommendations differ for PWH in terms of timing, dosing, and need to check for serological response. New vaccines are available and recommended for PWH for prevention of invasive pneumococcal disease, respiratory syncytial virus (RSV), COVID-19, mpox, and hepatitis B virus (HBV).

Summary

People with HIV experience persistent immune dysfunction, characterized by chronic immune activation and increased susceptibility to certain infections. To optimize potential of vaccines to reduce infection and infection-associated malignancies in PWH, strategies to improve vaccine responses and reduce vaccine hesitancy are necessary. While newer adjuvants show promise in enhancing immunogenicity, key questions remain regarding the durability of vaccine-induced protection and the ideal timing and necessity of booster doses for many vaccines.

Introduction

Human immunodeficiency virus (HIV) disrupts immune function primarily by depleting CD4 T lymphocytes, compromising both humoral and cellular immunity. Although combination antiretroviral therapy (cART) has transformed HIV care, enabling most patients to achieve undetectable viral loads and adequate CD4 counts, significant immune function differences persist. Immune recovery can be incomplete in patients with low nadir CD4 counts or delayed initiation of cART, due to inadequate CD4 cell reconstitution and additional defects in cell-mediated and humoral immunity [1–5]. Early cART initiation leads to significant but not complete normalization of immune dysregulation [3].

Even in the context of early cART and effective viral suppression, people with HIV (PWH) exhibit chronic immune activation. This is marked by elevated levels of pro-inflammatory cytokines and immune cells and is linked to the latent HIV reservoir [6, 7]. This chronic activation contributes to early immunosenescence, a state of immune aging that occurs earlier in PWH compared to the general population [8].

Immune profiles of virally suppressed PWH reveal distinct alterations, such as reduced percentages of CD4 + T cells, naïve T cells, memory B cells, and natural killer (NK) cells, along with increased proportions of CD8 + T cells, T helper 17 cells, short-lived plasmablasts, and monocytes. Impairments in B/T cell interactions, which are critical for memory B cell formation, and diminished IFN-gamma responsiveness further highlight these immune deficits [5].

Based on the above, it is not surprising that PWH – even those on suppressive cART – remain at increased risk for certain infections, most notably pneumococcal disease [9] and herpes zoster [10]. Similarly, the immunogenicity of vaccines in PWH is usually reduced, as evidenced by reduced seroconversion rates (SCR) and diminished antibody longevity [11, 12]. Predictors of poor vaccine response include the absence of cART, low CD4 count at the time of vaccination, a CD4 nadir below 200 cells/mm³, and higher HIV RNA levels at the time of vaccination [12].

Given these differences, vaccination guidelines for PWH differ from those of the general population. This review highlights updates to these guidelines, recent data, and remaining questions. Tables 1 and 2 provide descriptions of vaccine types and concepts used throughout the text. Table 3 provides a recommendation summary.

Table 1.

Definitions

Immunogenicity	Ability of a vaccine to induce an adaptive immune response (humoral and/or cell-mediated)
Reactogenicity	Tendency of a vaccine to produce expected, short-term adverse reactions such as pain at the injection site, fever, or fatigue
Adjuvant	Substance used in a vaccine to enhance immune response against the antigen. Common adjuvants include aluminum-based (HAV, HBV except Heplisav-B, 9vHPV, PPSV23), oil-in-water emulsion MF59 (influenza), Toll-like receptor (TLR) 4-agonist AS01 (Shingrix, RSV Arexvy), TLR9-agonist CpG 1018 (Heplisav-B)
Seroprotection	Antibody level above a pre-defined cut-off that indicates disease immunity
Seroconversion	A significant increase in antibody levels, often defined as a fourfold rise, or a change from a seronegative to seropositive state, that indicates an immune response to a vaccination or infection
Vaccine effectiveness	Percentage reduction in the rate of disease among vaccinated compared to unvaccinated individuals in real-world settings
Vaccine efficacy	Percentage reduction in the rate of disease among vaccinated compared to unvaccinated individuals in controlled clinical trial settings
Vaccine hesitancy	Delayed- or non-vaccination despite vaccine availability; influenced by factors like mistrust, misinformation, and concerns about safety or efficacy

Table 2.

Types of Vaccines

Vaccine Type	Description	Immune Response Generated	Examples	Notes
Live attenuated	Weakened organism able to replicate in humans with reduced pathogenicity but retained immunogenicity	B and T call responses, induce immunological memory (memory B cells and long-lived plasma cells)	MMR, yellow fever, live attenuated influenza vaccine (LAIV), varicella	Contraindicated when CD4 < 200 or 15%. Avoid LAIV in PWH regardless of CD4
Live nonreplicating	Weakened organism unable to replicate in humans	B and T cell responses, induce immunological memory	Modified Vaccinia Ankara (Jynneos)	Safe in PWH regardless of CD4
Whole inactivated	Killed organism, unable to replicate or cause disease	B and T cell responses, induce immunological memory	Inactivated polio vaccine (IPV), HAV	May have higher reactogenicity
Subunit (multiple types)
- Polysaccharide	Purified bacterial capsular polysaccharides from inactivated organism	T-cell independent, generate exclusively antibody-dependent response and do not induce immunological memory	PPSV23	Limited immune memory
- Protein-polysaccharide conjugate	Purified polysaccharides from inactivated organism conjugated to a protein carrier	Engage T-cells and promote generation of memory B cells and long-lived plasma cells	PCV15/20/21, MenACWY	Common carrier proteins are tetanus toxoid, diphtheria toxoid (DT), CRM197 (non-toxic variant of DT)
- Purified protein	Purified protein from inactivated organism	B and T cell responses, induce immunological memory	Inactivated influenza vaccine	Often require adjuvants to enhance immune response
- Recombinant protein	Antigen produced through recombinant DNA technology	B and T cell responses, induce immunological memory	RZV (Shingrix), recombinant influenza vaccine (RIV), Heplisav-B	Often require adjuvants to enhance immune response
- Virus-like particle (VLP)	Recombinant capsid proteins that self-assemble as a shell to form VLPs	B and T cell responses, induce immunological memory	HPV, HBV (Engerix-B, Recom-bivax-HB)	Closely resemble viral structure, 9vHPV is highly immunogenic
- Outer membrane vesicle	Spherical buds made from the outer membrane of gram-negative bacteria that contain membrane surface proteins and lipids, vaccines typically also contain recombinant proteins	B and T cell responses, induce immunological memory	4CMenB (Bexsero)	Strong immunogenicity due to bacterial membrane components
Toxoid	Inactivated toxins	B and T cell responses, induce immunologic memory	Diphtheria, tetanus	Neutralizes toxins rather than bacteria itself
mRNA	mRNA encoding antigen proteins encased in lipid nanoparticles	B and T cell responses, induce immunologic memory	SARS-CoV-2, RSV (mResvia)	Rapidly adaptable platform

Adapted from Pollard AJ, Bijker EM, ‘A guide to vaccinology: from basic principles to new developments.’ Nat Rev Immunol. 2021;21(2):83–100[118]

Table 3.

Summary of Vaccine Considerations for Adult PWH (vaccines featured in manuscript)

	Incidence/severity in PWH compared to non-PWH	Vaccine Immunogenicity in PWH compared to non-PWH	Whom to vaccinate		Serological Monitoring?	Notes
			General Population	PWH
Pneumococcal	↑ incidence[9]	↓ [18, 19]	19–64 yrs with risk factors; all 65 + yrs	All	No	See Fig. 1
Meningococcal	↑ incidence[22, 23]	↓ [28]/↔ [29]	MenACWY: with risk factors MenB: with risk factors	MenACWY: all MenB: with risk factors	No	See Box 1 for possible efficacy of 4CMenB in gonorrhea
Mpox	↑ incidence and severity[39, 41]	↓ [47–49]	Adults with potential for exposure	Adults with potential for exposure	No	See Box
HBV	↑ incidence and severity[27]	↓ conventional vaccine [55] ↔ TLR-9 adjuvanted vaccine [57, 58]	HBV nonimmune (anti-HBs < 10 mIU/mL) without HBV	HBV nonimmune (anti-HBs < 10 mIU/mL) without HBV	Yes	HepB-CpG is now preferred for PWH
HAV	↑ severity[27]	↓[61]	Adults at increased risk of infection or severe disease	All HAV nonimmune	Yes
HPV	↑ persistent HPV and related diseases[62, 63]	↓[65]	All up to 26 yrs, shared decision-making up to 45 yrs	All up to 26 yrs, shared decision-making up to 45 yrs	No	3-dose schedule recommended for all PWH
VZV	↑ incidence and severity	↔[74]	≥ 50 yrs; ≥ 19 yrs if immuno-compromised	≥ 18 yrs (≥ 19 yrs ACIP)	No	Live varicella vaccine contrain-dicated if CD4 < 200
RSV	Minimal data	Minimal data	Pregnant women weeks 32–36 yrs; 60–74 yrs with risk factors; all 75 + yrs	Pregnant women weeks 32–36 yrs; 60–74 yrs with advanced/untreated HIV or other risk factors; all 75 + yrs	No	Also FDA-approved for high-risk adults 50–59
COVID-19	↑ severity when CD4 < 350[94]	↓[88, 98, 99]	All	All	No	mRNA: reactogenicity
Influenza	Possible ↑ severity but data inconsistent[102–104]	↓[106, 107]	All	All	No	Live attenuated vaccine contraindicated

For more information see individual vaccination recommendations at www.cdc.gov/vaccines/index.html or DHHS Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV available at https://clinicalinfo.hiv.gov/

Pneumococcus

Disease Risk

PWH, even those who are virally suppressed with CD4 counts > 500 cells/mm³, are at increased risk of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP). In a large recent Dutch study, incidence rates of IPD and CAP were found to be 4 and 5-times higher in people with well-controlled HIV compared to the general population [9].

Recommendations

Recommendations continue to evolve with the approval of new, higher valent conjugate vaccines. All PWH should be vaccinated regardless of CD4 count or age. For those who have not yet been vaccinated, options include one dose of the protein conjugate vaccine PCV20, one dose of the newly approved PCV21 (Capvaxive), or one dose of PCV15 followed at least 8 weeks later by the polysaccharide vaccine PPSV23. There is no need for booster doses so long as patients receive one of these protein conjugate vaccines [13, 14]. See Fig. 1 for recommendations in patients who have received one or more doses of a pneumococcal vaccine.

Fig. 1.

Pneumococcal Vaccination Guidelines for Adults with HIV. Adapted from Spach D. National HIV Curriculum: Basic HIV Primary Care. Immunizations in Adults—Pneumococcal Vaccination. https://www.hiv.uw.edu/custom/primary-care/immunizations/11 2024 [17]

PCV21 contains 8 serotypes not covered by prior vaccines and was recommended as an option by the ACIP as of June 2024 [14]. Based on 2018–2022 surveillance data, it covers serotypes responsible for approximately 81% of IPD cases in adults with a risk-based indication for vaccination (including PWH), compared to 58% for PCV20 [15] and 57% for PCV15 + PPSV23 [16]. Notably, PCV21 does not include serotype 4, which is included in the other vaccines. While serotype 4 causes less than 2% of IPD cases in the immunocompromised population overall, it causes up to 30% of cases among people aged < 65 years with homelessness, substance use disorders, cigarette smoking, or chronic lung disease in parts of the western United States including Colorado, New Mexico, the Navajo Nation, Oregon, and Alaska [14]. For adults in these populations, PCV20 or PCV15 plus PPSV23 is expected to provide more appropriate coverage than PCV21 and should be strongly considered. Clinical guidance will be updated as pneumococcal disease epidemiology evolves, and providers can use the CDC’s interactive guideline tool for the most up-to-date recommendations (https://www2a.cdc.gov/vaccines/m/pneumo/pneumo.html).

Safety and Immunogenicity Data

Pneumococcal vaccines are immunogenic in PWH, though there is evidence of lower seroconversion rates (SCRs) and more rapid decline in antibody levels in PWH (including those on cART) as compared to non-PWH, particularly among those with nadir CD4 counts < 200 cells/mm³ [18, 19].

PWH-specific safety and immunogenicity data is available for PCV15 + PPSV23 [20] and for PCV21, supporting their use. PCV21 elicits comparable immune responses to PCV15 + PPSV23 for all 13 shared serotypes and was immunogenic for the 8 unique serotypes [21]. PCV-20 has not been studied specifically in PWH; in healthy controls, it met noninferiority criteria as compared to PCV13 but was found to be slightly less immunogenic for most shared serotypes [13].

New Developments, Personal Insights, and Remaining Questions

Based on the above data, we believe PCV21 is the best option when available due to its broader serotype coverage and strong immunogenicity profile in PWH. For adults at increased risk of serotype 4 disease, we agree with the recommendation for regimens that specifically cover this serotype (PCV15 + PPSV23 or PCV20 alone). However, determining the regional prevalence of serotype 4 disease remains challenging, particularly in areas without comprehensive IPD surveillance. The development of 24- and 31-valent vaccines with even broader coverage (including serotype 4) is underway, and these options could become available within the next one to two years, potentially resolving this issue.

Meningococcus

Disease Risk

PWH face an estimated sixfold higher risk of invasive meningococcal disease (IMD) compared to non-PWH [22], with the risk increasing to 13-fold among those meeting the CDC’s AIDS definition [23]. IMD cases among PWH have more than doubled in 2022 as compared to prior years (36 cases in 2022 as compared to 5 to 15 per year over the previous 5 years) [24, 25], with a striking increase in bacteremic sequence type 1466 serogroup Y disease in 2023 and 2024 [26].

Recommendations

Regardless of CD4 count, all PWH are recommended to receive two doses of a polysaccharide conjugate MenACWY vaccine (Menveo [MenACWY-CRM197] or MenQuadfi [MenACWY-TT]) eight weeks apart, followed by boosters every five years. The recombinant protein-based meningococcal B (MenB) vaccine is recommended only for those with additional risk factors such as asplenia or complement deficiency (and for consideration in young people or those living in dormitories/barracks) [27].

Safety and Immunogenicity Data

Older studies of the Men-C vaccine and the MenACWY-D vaccine (now discontinued) suggested decreased immunogenicity in PWH, particularly among those with low CD4 counts [28]. However, a recent study of patients with well-controlled HIV who received 2 doses each of both the MenACWY-CRM and the 4CMenB vaccines demonstrated excellent antibody responses to all strains, similar to those of the immunocompetent population [29].

New Developments, Personal Insights, and Remaining Questions

A pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp) was FDA-approved and recommended for use by the ACIP in late 2023 for those who have indications for MenACWY and MenB [30]. Safety and immunogenicity studies have not been completed in PWH. If MenB is indicated, we favor using an outer membrane vesicle (OMV) vaccine (4CMenB/Bexsero) over MenB-FHbp (Trumenba) for the OMV vaccine’s potential efficacy in reducing gonorrhea incidence (see Box 1). MenB-FHbp has no efficacy in preventing gonorrhea. Pentavalent vaccines with an OMV vaccine component are in development [31].

BOX 1.

Interest in the meningococcal B vaccine’s potential to prevent gonorrhea was sparked after a 2017 retrospective case–control study in New Zealand showed that the outer membrane vesicle (OMV) vaccine MeNZB was 31% effective against gonorrhea in young adults [32]. This finding has since been replicated in several observational studies in people without HIV, with OMV vaccines (but not non-OMV vaccines [33]) demonstrating around 22–46% effectiveness against gonorrhea [34]. A 2023 observational case control study in Italian PWH similarly demonstrated 44% effectiveness of 4CMenB (the OMV-vaccine Bexsero) against gonorrhea [35]. On this basis, the UK’s Joint Scientific Committee on Vaccination and Immunisation has advised the UK government that the 4CMenB vaccine should be routinely offered to those at high risk of gonorrhea [36]. Similar recommendations have not been made in the United States because the efficacy of meningococcal vaccines in protecting against gonorrhea has not been definitively demonstrated in randomized trials. One open-label randomized trial (DOXYVAC, France, 2021–2022) assessed 4CMenB’s efficacy in reducing incidence of gonorrhea in men who have sex with men who did not have HIV; the receipt of 2 doses of vaccine vs no vaccine showed a trend towards reduced incidence of first episode of gonorrhea but this did not reach statistical significance (aHR 0.78, p = 0.061) [37]. Additional RCTs are underway, including the GoGoVax trial, which is investigating the efficacy of 4CMenB in PWH and non-PWH [38], and ongoing trials for gonorrhea-specific vaccines.

Mpox Virus

Disease Risk

Whether PWH have increased risk for mpox is uncertain, but a large percent of mpox cases occur in PWH. PWH with lower CD4 counts, especially < 50 cells/mm³, are at increased risk of severe infections and disseminated disease, potentially leading to hospitalization, prolonged disease [39], or death [40–42].

Recommendations

The modified vaccinia Ankara (MVA) vaccine (JYNNEOS) is a nonreplicating live virus vaccine recommended for people at risk for exposure to mpox (see box). Vaccination during mpox infection or after recovery is not recommended currently. MVA became available in the US through Emergency Use Authorization (EUA) during the Clade II mpox outbreak in 2022, has been recommended by the ACIP since 2023, and became commercially available in the US in 2024. It is approved for smallpox and mpox prevention in adults 18 and older, including PWH with any immune status. The vaccine can be used for prevention or post-exposure prophylaxis. For prevention, a 2-dose series (4 weeks apart) is administered subcutaneously. Intradermal dosing uses a lower dose and can be considered if vaccine supply is limited. Additional or booster doses are not currently recommended for people at risk of community mpox transmission, since recent data shows post vaccination mpox is rare (< 1% of vaccinated people) and less severe [43]. For post-exposure prophylaxis (PEP), MVA should be offered within 4 days (but can be given up to 14 days post exposure), to prevent mpox or reduce severity. In addition to MVA, Vaccinia immune globulin (VIGIV) may be considered as PEP for patients with severe immunodeficiency in consultation with the CDC. With regard to vaccine coadministration, the CDC suggests administering COVID-19 and JYNNEOS vaccines 4 weeks apart, particularly in young men, if the patient is not at risk for severe disease because of concerns about myocarditis.

BOX 2. [44–46].

Current recommendations on whom to vaccinate based on risk for community transmission of mpox (based on February 2023 and October 2023 ACIP recommendations)

• Gay, bisexual, and other men who have sex with men, transgender or nonbinary people who in the past 6 months have had one of the following:

  • a new diagnosis of ≥ 1 sexually transmitted disease
  • more than one sex partner
  • sex at a commercial sex venue
  • sex in association with a large public event in a geographic area where mpox transmission is occurring

• Sexual partners of people with the risks described above

• People who anticipate experiencing any of the above

• Travel to countries* with person-to-person Clade I mpox spread and expected:

  • Sex with a new partner
  • Sex at a commercial sex venue, such as a sex club or bathhouse
  • Sex in exchange for money, goods, drugs, or other trade
  • Sex in association with a large public event, such as a rave, party, or festival

*See CDC website but as of November 16, 2024, these countries include: Burundi, Central African Republic, Democratic Republic of the Congo, Republic of the Congo, Rwanda, and Uganda

ACAM 2000 is a replication competent live vaccina virus vaccine available only through the CDC. It is not used routinely in the ongoing Clade II mpox outbreak due to due to increased potential for side effects as well as restrictions on who can receive it [44].

Safety and Immunogenicity Data

Modified Vaccinia Ankara is safe and effective to use in PWH with any immune status. No difference in side effects have been observed in PWH. No correlate of protection exists for mpox, but peak immunity occurs about 14 days after the 2nd dose with neutralizing antibody titers declining [dramatically] by 6 months. Three clinical trials of MVA in PWH including one enrolling people with a history of AIDS (including approximately 20% with CD4 < 200 at enrollment) showed neutralizing antibody responses similar to those of the general population [47–49]. However, a US study suggests vaccine effectiveness may be lower in people with immunocompromise (primarily HIV) (70.2% among immunocompromised compared to 87.8% among immunocompetent) [50].

New Developments, Personal Insights, and Remaining Questions

Remaining questions include whether additional or booster doses of MVA would benefit PWH and whether people with a history of past mpox would benefit from vaccination. A recent US study including 2021–24 data comparing mpox cases in fully vaccinated patients to unvaccinated found that a lower proportion of fully vaccinated patients with mpox were PWH (29% v 54%) (p < 0.001) [43]. Available data suggest that mpox infection post vaccination may relate to increased exposure risk rather than waning immunity [51]. A third dose was discussed by the ACIP in June 2023 and no recommendation was made for a third dose (even for those with advanced HIV) with the caveat that continued study of vaccine effectiveness in PWH as well as disease severity in fully vaccinated individuals is needed [52]. Until then, the evidence supports focusing on improving vaccine coverage of populations (particularly those with disparate vaccination rates) with risk for mpox acquisition rather than additional doses, even in immunocompromised.

Vaccine effectiveness against clade I is not known because widespread vaccine rollout has not occurred in African countries affected outside of a study of heath care workers [53]. However, animal models suggest effectiveness and MVA is approved for prevention of mpox regardless of clade.

Hepatitis B Virus (HBV)

Disease Risk

PWH have increased risk for developing chronic HBV infection (defined as hepatitis B surface antigen (HBsAg) detected for > 6 months) as they have higher viremia and lower chance of spontaneous resolution after acute infection. PWH also have increased risk for disease progression including liver-related morbidity and mortality and hepatocellular cancer [54]. Relevant to vaccination, PWH are also at increased risk for the presence of isolated antibody to hepatitis B core antigen (anti-HBc), in the absence of HBsAg or anti-HBs, which often represents past HBV infection and resolution but with waning anti-HBs levels [27].

Recommendations

A hepatitis B vaccine series is recommended for all susceptible PWH without chronic HBV infection, including those never vaccinated, partially vaccinated and nonresponders to vaccination. Note that testing for vaccine response is recommended for PWH, with correlate of protection being anti-HBs ≥ 10 mIU/mL [27]. For initial vaccine series, recombinant HBsAg (20 mcg) vaccine with CpG (HepB-Cpg), a TLR-9 agonist adjuvant (HEPLISAV-B) given as a 2-dose series is preferred [27]. Other options include conventional recombinant HBsAg vaccines (e.g. Engerix-B, Recombivax HB), often given as double dose 3-dose series, or recombinant combined HBsAg and HAV vaccine (Twinrix). A 3-antigen recombinant HBV vaccine was also approved in 2021 (PreHevbrio) but is being voluntarily withdrawn from U.S. market due to bankruptcy.

For vaccination of conventional vaccine nonresponders, we recommend HepB-CpG (HEPLISAV -B) 2- or 3- dose series (see below).

PWH and isolated anti-HBc should receive one standard dose of HBV vaccine, with serologic confirmation of response. If anti-HBs is < 100 mIU/mL, the full HepB vaccine series should be completed [27].

Hepatitis B vaccine is also recommended for post-exposure prophylaxis with hepatitis B immune globulin for unvaccinated individuals.

Safety and Immunogenicity Data

Conventional HBV vaccines are very safe and have been in use since 1986, but for PWH seroprotection varies from 34–93% with 3 doses depending on the study and population; low CD4 count and HIV viremia are predictors of nonresponse [55]. Immunity may also wane over time leaving PWH susceptible to infection [56]. A recent prospective clinical trial in people with well controlled HIV demonstrated that HepB-CpG (HEPLISAV-B) is safe and effective in PWH and that the addition of the TLR-9 agonist adjuvant results in superior seroprotection. Three doses of HepB-CpG achieved 100% seroprotection response (SPR) in PWH and no prior HBV vaccination, with 98.5% % achieving seroprotection after 2nd dose [57]. For nonresponders, both 2 and 3 doses of HepB-CpG achieved superior seroprotection response over 3 standard doses of conventional vaccine in an open-label randomized clinical trial (93%, 99%, and 81% respectively), with participants receiving HepB-CpG achieving seroprotective response earlier [58].

New Developments, Personal Insights, and Remaining Questions

We favor 3 doses of HepB-CpG (over 2 doses) in PWH with documented vaccine nonresponse, particularly those at high risk of HBV infection or with predictors of poor vaccine response such as low CD4 count and older age. While durability data of is not yet available, 96% who received 3 doses achieved anti-HBs > 100 IU/ml compared to 70% with 2 doses, and titers > 1000 IU/ml were achieved in 78% and 26% respectively [58]. In other studies of hepatitis B vaccination, high titer predicts durability of response [59]. We recognize that 2 doses may have benefits in terms of completion rates [60].

Hepatitis A Virus (HAV)

Disease Risk

PWH are at risk of more severe HAV infection (particularly in the setting of underlying liver disease) and more protracted disease.

Recommendations

An inactivated hepatitis A vaccine series is recommended for all susceptible PWH including those never infected, never vaccinated, partially vaccinated, and nonresponders to vaccine (correlate of protection considered to be total anti-HAV ≥ 10 mIU/mL). Available formulations include Vaqta (2 doses), Havrix (2 doses), and Twinrix (given with recombinant HBV surface antigen as 3 dose series). Revaccination may be considered in PWH who fail to achieve total anti-HAV ≥ 10 mIU/mL, with testing recommended 1–2 months after an initial series [27]. If revaccination does not achieve seroconversion, additional vaccination is not recommended [61]. Preventative counseling or immunoglobulin G(IgG) in event of known exposure could be considered.

Hepatitis A vaccine is also recommended for post-exposure prophylaxis with IgG for non-immune individuals ideally within 2 weeks of exposure [61].

Safety and Immunogenicity Data

There are no excess safety risks with HAV vaccination in PWH. The correlate of protection against HAV is achieved with vaccination less commonly in PWH than the general population, particularly in people with lower CD4 counts or elevated HIV RNA [61].

Human Papillomavirus (HPV)

Disease Risk

Persistent infection with high-risk HPV is more common in PWH and leads to increased rates of HPV-related diseases, including genital warts, oropharyngeal, cervical, and anal cancer, and precancerous lesions. The risk of developing HPV-associated cervical cancer, for instance, is estimated to be sixfold higher in women with HIV as compared to women without HIV [62] and anal cancer up to 85 times higher in MSM with HIV as compared to men without [63]. The risk of HPV-associated complications increases with decreasing CD4 counts [27].

Recommendations

The only HPV vaccine currently available in the United States is the 9-valent vaccine (9vHPV, Gardisil-9), which offers protection against seven oncogenic serotypes (16, 18, 31, 33, 45, 62, 58) and two that cause genital warts (6, 11). It is an adjuvanted subunit vaccine containing HPV L1 capsid proteins that self-assemble into noninfectious virus-like particles (VLPs).

A three-dose series (0, 1–2, and 6 months) is recommended for all PWH aged 9–13, ideally before the onset of sexual activity. This differs from the ACIP two-dose series recommended in young people without HIV [45]. Catch-up vaccination is recommended through age 26 and, with shared clinical decision-making, can be considered through age 45 [27]. Revaccination with 9vHPV can be considered in patients who were vaccinated with the earlier bivalent or quadrivalent vaccines, though vaccination of older individuals has not been shown to be an effective strategy outside of isolated clinical trials conducted in relatively HPV-naïve individuals [64]. Vaccination does not negate the need for guideline-recommended anal and cervical cancer screenings.

Safety and Immunogenicity

High-quality efficacy studies are not available in PWH, but the vaccine’s safety and the immunogenicity of the three-dose schedule have been well-established, with stronger immune responses among those with higher CD4 counts [65]. It has shown remarkable effectiveness against persistent oncogenic HPV infection when administered early [66].

New Developments, Personal Insights, and Remaining Questions

Recent trials have shown that single-dose vaccination (instead of two doses) has excellent efficacy against persistent cervical high-risk HPV infections in immunocompetent females [67, 68]. While there is no published data on the immunogenicity or efficacy of 1- or 2-dose schedules for PWH or men, preliminary data from an ongoing South African trial suggest that a single dose of the bivalent vaccine has a similar efficacy in preventing persistent HPV infections 24 months after vaccination in adolescent girls with and without HIV [62, 69]. There are ongoing clinical trials to validate the use of single-dose and two-dose HPV vaccination in PWH.

Recent observational literature indicates that both systemic and intralesional HPV vaccination may have a therapeutic role for anogenital wart treatment, especially for patients who have not yet been vaccinated, though the mechanism for how this occurs is unknown, and further study is needed [70, 71]. Adjuvant use of the quadrivalent vaccine was studied in PWH being treated for cervical and anal precancer in two separate randomized clinical trials but did not reduce rates of lesion recurrence or persistence after surgical treatment [72].

Varicella-Zoster Virus (VZV)

Disease Risk

Most adults born in the US have immunity to VZV through prior infection (chickenpox) or childhood vaccination (most children born after 2005 vaccinated). PWH are at increased risk of reactivation of latent VZV resulting in herpes zoster (shingles) at any age, particularly those with CD4 count < 200 or HIV viremia. Although cART lessens the risk it does not eliminate it [73]. PWH are also at increased risk of zoster-related complications including post herpetic neuralgia, disseminated disease, central nervous system disease, and acute retinal necrosis or progressive outer retinal necrosis. As in the general population, advanced age is a risk for reactivation, which is notable since more than half of people with HIV in US are over age 50.

Recommendations

Recombinant zoster vaccine (RZV), containing recombinant VZV glycoprotein E and adjuvant AS01B (Shingrix), is approved as a 2-dose series with doses given 2–6 months apart. It is approved for all PWH 18 years or older and recommended by the ACIP for those aged 19 or older with immunity to VZV through past infection or childhood vaccination [45]. Timing of vaccination in people initiating ART is controversial, with some experts recommending delaying vaccination until virologic suppression or even CD4 cell recovery. Vaccination is recommended for PWH with a history of shingles (though not during acute disease or during a period of VZV-related inflammatory eye disease symptoms), past receipt of a live zoster vaccine (Zostavax, no longer available in US), or past varicella vaccination.

VZV-seronegative adults with CD4 ≥ 200 cells/mm³ should receive varicella vaccination (Varivax^™, 2 doses, administered 3 months apart); however, this live attenuated vaccine is contraindicated in more severely immunocompromised PWH [27].

VariZIG is also available for post-exposure prophylaxis of susceptible individuals, and if given should result in a delay in vaccination.

Safety and Immunogenicity Data

Although studied in PWH as a 3-dose series [74], the vaccine elicited strong VZV gE-specific cell-mediated and humoral immune responses after 2 doses including in the subset of PWH with CD4 < 200 cells/mm³. Side effects were as common as in the general population including injection site pain, fatigue, myalgia, headache, and fever [75].

New Developments, Personal Insights, and Remaining Questions

For people with HIV initiating ART, we favor administration of RZV after achievement of viral suppression rather than waiting for CD4 cell recovery.

There is no recommendation for booster doses of RZV currently. Good humoral and cell-mediated vaccine responses have been demonstrated out to 10 years in the long term follow up of the registrational trials of RZV in older adults [76], but vaccine durability in PWH is unknown.

The current recommendation for RZV includes people who received childhood varicella vaccination. While declines in age-specific herpes zoster incidence have been observed as varicella-vaccinated cohorts age, the risk of herpes zoster is not eliminated, and vaccine-strain zoster has been documented.

Additional vaccine approaches such as mRNA vector and TLR-9 agonist adjuvant are in early phase clinical trials.

Respiratory Syncytial Virus (RSV)

Disease Risk

Minimal data are available on the incidence or severity of RSV in adults with HIV. A South African epidemiological study found that the incidence of severe RSV requiring hospitalization was over ten times higher in people with HIV compared to those without [77], but fewer than half of the participants with HIV were on ART, making this poorly generalizable.

Recommendations

Recommendations for PWH are the same as for the general population unless they have advanced or untreated HIV (CD4 < 200 cells/mm³, history of AIDS-defining illness without immune reconstitution, clinical manifestations of symptomatic HIV), which places them in the CDC’s moderately to severely immunocompromised category. A one-time dose of the RSV vaccine is recommended for pregnant women who are between weeks 32 and 36 during September – January, for all adults aged ≥ 75, and for adults aged 60–74 with increased risk of severe RSV disease. Risk factors for severe disease include moderate to severe immunocompromise and chronic medical conditions (such as diabetes mellitus, obesity, frailty, lung, liver, and heart disease) [79].

Three vaccines are approved for preventing RSV-associated lower respiratory tract disease (LRTD) – RSVPreF3 OA (Arexvy), RSVPreF (Abrysvo), and mRNA-1345 (mResvia). The ACIP gives no preference among them [79]. mRNA-1345 is the first approved mRNA vaccine apart from SARS-CoV-2, RSVPreF3 AO is a monovalent AS01_E-adjuvanted recombinant protein subunit vaccine, and RSVPreF is a bivalent recombinant protein subunit vaccine and the only vaccine approved for pregnant women.

Safety and Immunogenicity

PWH have been included in some safety and efficacy studies but have been inconsistently categorized as immunocompetent vs immunocompromised, and PWH-specific data does not exist. Trials in immunocompetent populations demonstrate around 80–90% efficacy against RSV-LRTD with ≥ 3 lower respiratory symptoms in the first season after vaccination for all vaccines [79–82], and a recent case–control study that included immunocompromised patients showed vaccine effectiveness of 75% in preventing RSV-associated hospitalization over the first season [83]. Efficacy is reduced over two seasons, particularly for the mRNA vaccine (48% for mRNA-1345 [81], 67% for RSVPreF3 OA [84], and 78% for RSVPreF [85]). There appears to be an elevated risk of Guillain-Barré Syndrome (GBS) in individuals aged 65 and older following vaccination with protein subunit RSV vaccines, prompting FDA-mandated safety labeling changes (see Box 3) [78]. No cases of GBS have been reported after receipt of mRNA-1345 [79].

Box 3. Guillain Barre Syndrome (GBS) and RSV Vaccines: A Closer Look.

Early post-marketing data from the Vaccine Adverse Event Reporting System (VAERS) has raised concerns about a possible association between GBS and RSV vaccines. Preliminary reports show a higher incidence of GBS within 42 days of receiving the RSVPreF and RSVPreF3 OA vaccines (4.4 and 1.8 cases per million doses, respectively) when compared to the general background rates of GBS (0.43–0.54 cases per million vaccine doses) [86]. Recent analyses using Medicare claims data with rigorous medical record review have similarly suggested a roughly 2 to 2.5-fold increase in the risk of GBS in individuals aged 65 and older following vaccination with the RSVPreF3 OA and RSVPreF vaccines. Due to the low background incidence of GBS, the absolute increase in risk remains very low, with fewer than 10 additional GBS cases per one million vaccine doses administered. Notably, no difference in GBS risk was observed between individuals who received RSV vaccines alone and those who received them concurrently with other recommended immunizations [87]. It is important to note that these findings remain preliminary, and that available evidence is not sufficient to establish a causal relationship. There is no evidence for increased risk of GBS in pregnant women who receive RSVPreF. The CDC and FDA continue to closely monitor RSV vaccine safety, and additional analyses are underway. For PWH specifically, no data exist regarding GBS following RSV vaccination. Updates can be found at https://www.cdc.gov/vaccine-safety/vaccines/rsv.html

New Developments, Personal Insights, and Remaining Questions

We favor administration of RSVPreF3 OA (Arexvy) in PWH, particularly in those with low CD4 counts at the time of vaccination, given the possibility that the adjuvant enhances immunogenicity. Pregnant women with HIV should receive RSVPreF. We suggest vaccination of PWH aged 60–75 years with well-controlled HIV and without other clear comorbidities if they express interest. We recommend RSV vaccination in PWH who are ≥ 75 years old. Whether additional doses may be needed is under investigation.

SARS CoV-2 Infection (COVID-19)

Disease Risk

The incidence rate of SARS-CoV-2 infection in PWH does not differ from that of the general population. Prior to widespread vaccination, rates of severe disease and death were noted to be higher in PWH, particularly in those with lower CD4 + T cell counts at the time of infection and at nadir [88–92]. Data are mixed on severity in PWH with high CD4 counts, but one study indicated decreased odds of hospitalization in PWH with CD4 ≥ 500 cells/mm³ even early in the pandemic, possibly due to improved engagement in healthcare [93]. After vaccination, it appears that the risk of severe illness requiring hospitalization does not differ by HIV status in those with CD4 ≥ 350 cells/mm³ but is higher in those with CD4 < 350 cells/mm³ [94]. PWH appear to be at increased risk for post-COVID conditions (PCC) [95] (though risk is reduced by vaccination), and for breakthrough infection after full vaccination [94].

Recommendations

Recommendations for PWH are the same as for the general population unless they have advanced or untreated HIV, which places them in the CDC’s moderately to severely immunocompromised category [96]. Guidelines continue to change, and clinicians should always consult the CDC for the most updated recommendations at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html. There are currently two monovalent mRNA options (Moderna and Pfizer) available and one adjuvanted protein subunit vaccine (Novavax).

As of this writing, for people less than age 65 without moderate to severe immunocompromise, one dose of either updated mRNA vaccine (or two doses of Novavax) is recommended for initial vaccination. Following initial vaccination in this group, one dose of an updated mRNA vaccine or Novavax is recommended yearly.

For people ≥65, two doses of any COVID-19 vaccine separated by 6 months is recommended annually regardless of vaccination history. Unvaccinated individuals who initiate vaccination with Novavax should receive two doses of Novavax followed by a third dose of any COVID-19 vaccine 6 months later.

For those with moderate to severe immunocompromise, 3 doses of an mRNA vaccine or 2 doses of Novavax followed a third dose of any vaccine is recommended for initial vaccination, and at least two doses of an updated vaccine are recommended yearly [96].

The recombinant human monoclonal antibody pemivibart, an attachment inhibitor targeting the SARS-CoV-2 spike protein, has EUA for pre-exposure prophylaxis in immunocompromised people who might not respond adequately to vaccination, provided the national frequency of variants with substantially reduced susceptibility to pemivibart remains below 90% [97].

Safety and Immunogenicity

MRNA and protein-adjuvant vaccines have been found to be safe, effective, and well-tolerated among PWH [98]. As compared to those without HIV, PWH (even among those with adequate CD4 counts) appear to have a slightly reduced humoral response to both natural infection and vaccination, with a faster decline in antibody levels [88, 98, 99]. No measures of vaccine-effectiveness specific to PWH are available, but the effectiveness of the 2023–2024 COVID-19 vaccine in preventing hospitalization among immunocompetent adults was found to be about 50% within the first 119 days post-vaccination [100].

New Developments, Personal Insights, and Remaining Questions

We agree with the CDC’s recent recommendation to administer two doses (spaced about 6 months apart) of the updated annual vaccine to those with advanced or untreated HIV and to those over age 65. Younger people with well controlled HIV should receive an annual dose of the COVID-19 vaccine. It remains to be seen whether these recommendations will be fully adopted given COVID-19 vaccine fatigue and reactogenicity that is particularly associated with the mRNA vaccines [101].

Influenza A & B Viruses

Disease Risk

Incidence of influenza infection appears similar among people with and without HIV. Some studies have shown increased rates of hospitalization, duration of illness, and mortality among PWH [102, 103], though these studies have included high numbers of people with advanced disease and the signals for increased severity have not been uniformly observed [104].

Recommendations

All PWH should receive one dose of the annual influenza vaccine. Recommendations differ based on age but not on degree of immunosuppression. Adults younger than 65 are recommended for either the inactivated or recombinant influenza vaccines, and adults aged ≥ 65 should receive either the high-dose inactivated vaccine, recombinant vaccine, or adjuvanted inactivated influenza vaccine [105]. The live attenuated influenza vaccine is not recommended for any PWH.

Safety and Immunogenicity

Immunogenicity, safety, and efficacy studies have generally shown good results in PWH with adequate CD4 counts, though multiple studies suggest decreased antibody responses following standard-dose inactivated influenza vaccines compared to non-PWH [106]. Patients with low CD4 counts have consistently poor antibody responses; in patients with CD4 counts < 100 cells/mm³, the response is nearly absent [107]. The high-dose and adjuvanted vaccines result in improved seroprotection rates, but there is insufficient evidence for increased efficacy of these strategies to warrant their recommendation in younger PWH [105].

New Developments, Personal Insights, and Remaining Questions

A recent large epidemiologic study of Kaiser Permanente patients indicated that the recombinant vaccine, which has a higher antigen dose, provided about 15% greater protection against PCR-confirmed influenza in all-comers aged 50–64 as compared to the standard dose inactivated vaccine, and 10% greater protection in those aged 18 to 49 [108]. Based on these data, we consider administering the recombinant vaccine (if available) to younger PWH, particularly those with lower CD4 counts. The development of vaccines that target less variable virus structures is underway [109]. Given that fluctuating effectiveness of the seasonal vaccines against drifted or pandemic strains can contribute to vaccine hesitancy (see Box 4), this is of particular importance.

BOX 4.

Vaccine hesitancy was listed as a top 10 threat to world health by the WHO in 2019 [110] and continues to increase; about 22% to 42% of adults in the general US population and 27–38% in PWH across various settings report at least some degree of hesitancy [111, 112]. Misinformation and (intentionally incorrect) disinformation amplified on social media have led to increasing doubts of vaccine safety, and research has shown that social media-driven anti-vaccine organization is associated with declining vaccination coverage [113]. Relatedly, skepticism about vaccine effectiveness has grown and trust in health providers as reliable sources of information has fallen [114]. New vaccines and policies often prompt questions and lead to increased hesitancy, which was particularly true in the context of the rapid development of the COVID-19 vaccines and surrounding politics and polarization.

Hesitancy in PWH is associated with minority racial and ethnic status (particularly among Black PWH as a response to historical injustices), female sex, and young age [111, 115]. In the case of the COVID-19 vaccine, being politically conservative and identifying as an “anti-vaxxer” have been associated with greater hesitancy [111].

Combating misinformation and addressing hesitancy are complex problems that require collaboration between the public health and medical communities and social media platforms, but individual providers can be highly influential for the hesitant patient. We recommend using evidence-based tactics including: 1) framing messages in terms of gain and appealing to altruism (e.g., “Getting the vaccine will protect you and your loved ones”); 2) making strong and consistent recommendations; 3) using presumptive language (e.g., “Today you need the HPV vaccine,” instead of “Would you like the HPV vaccine?”); 4) maintaining up-to-date knowledge on vaccine schedules, efficacy, and safety; and 5) responding to patient concerns with curiosity and without judgment. Similarly, evidence-based organizational tactics include: 1) implementing standing orders for nursing or pharmacy-administered vaccines; 2) presenting performance metrics to clinicians; 3) sending direct reminders to patients about upcoming vaccinations; 4) providing educational materials to patients and staff; and 5) using EMR prompts at the point-of-care [116]. Addressing hesitancy among office staff is also crucial.

MMR, Tdap, Hib

We do not address the measles-mumps-rubella (MMR), tetanus-diphtheria-acellular pertuss (Tdap), or haemophilus influenza type b (Hib) vaccines in detail, as recommendations have remained unchanged in the past five years. However, increased frequency of measles outbreaks due to declining vaccination rates underscores the importance of ensuring that PWH have documented immunity to measles. Acceptable evidence of immunity includes being born before 1957, documentation of two prior MMR doses, or positive antibody titers. A recent cross-sectional study reported a measles seroprevalence of 70.3% among PWH at a Nebraska HIV clinic – substantially lower than earlier studies showing 90–95% seroprevalence [117]. As the MMR vaccine is live attenuated, it is contraindicated in those with a CD4 counts < 200. However, PWH with CD4 counts ≥ 200 for at least 6 months who lack immunity should receive two doses of the vaccine. Notably, the measles, mumps, rubella, varicella (MMRV) vaccine, available since 2005, has not been studied in PWH and should not be used [27]. For Tdap, PWH should follow the same vaccination schedule as adults without HIV. The Hib vaccine is not routinely recommended for PWH unless specific indications are present, such as anatomic or function asplenia or a history of hematopoietic stem cell transplant) [45].

Conclusion

Even with optimal treatment, PWH experience persistent immune dysfunction, characterized by chronic immune activation and increased susceptibility to certain infections. Vaccination tailored to their unique needs is a critical component of preventive care to limit both infection and infection-associated malignancy. While newer adjuvants like TLR-9 agonists show promise in enhancing immunogenicity, key questions remain regarding the durability of vaccine-induced protection and the ideal timing and necessity of booster doses for many vaccines.

Simplifying vaccine schedules wherever possible – for instance, using newer pneumococcal vaccines with broader serotype coverage – can help improve adherence, while designing vaccines that reduce reactogenicity and target less variable viral components to reduce year-to-year fluctuations in effectiveness can foster greater public trust.

Ultimately, progress will depend on integrating these scientific advancements with practical and clear guidelines, empathetic provider communication, and organizational efforts to increase vaccine uptake. Only by doing so can we fully realize the benefits of modern vaccine science and improve long-term health outcomes for people with HIV.

Data Availability

No datasets were generated or analysed during the current study.