Pneumococcal immunization in adults with HIV

INTRODUCTION — Pneumococcal infections, including pneumonia and invasive disease such as bacteremia and meningitis, have been a major source of morbidity and mortality since the beginning of the human immunodeficiency virus (HIV) epidemic, leading many experts to endorse use of pneumococcal vaccine for primary prevention in patients with HIV [1]. However, the efficacy of pneumococcal vaccine in this patient population has been debated for many years [2]. In addition, pneumococcal vaccines are serotype-specific, so efficacy will also vary depending on the prevalent serotypes within the community.

This topic addresses data on the use of polysaccharide and conjugate pneumococcal vaccines in patients with HIV and suggestions for primary prevention. Data on the use of pneumococcal vaccines in the immunocompetent host and in individuals with other types of immune compromise are found elsewhere (see "Pneumococcal vaccination in adults", section on 'Approach to vaccination'). Advice on the use of other vaccines in patients with HIV is discussed in detail elsewhere. (See "Immunizations in persons with HIV" and "Prevention of hepatitis B virus infection in adults with HIV".)

EPIDEMIOLOGY OF PNEUMOCOCCAL DISEASE — Pneumococcal pneumonia and meningitis are leading causes of morbidity and mortality among patients with HIV worldwide and treatment is complicated by the increasing incidence of drug-resistant pneumococcal strains [3,4]. The overall incidence of invasive pneumococcal disease was 677 cases per 100,000 person-years in patients with HIV [3]. The case fatality rate of invasive disease ranges from 8 percent with pneumococcal bacteremia to 50 percent with meningitis [5,6].

A retrospective study performed in San Francisco, prior to the era of potent antiretroviral therapy (ART), found that the rates of pneumococcal bacteremia were approximately 100-fold greater in patients with HIV compared with those who were not infected with HIV [1]. In addition, recurrent invasive pneumococcal disease is common, occurring in up to 25 percent of patients within a year after the initial episode [7].

Risk factors — The most important risk factor for developing pneumococcal infections is the level of immunosuppression [7-10]. In one trial of pneumococcal vaccine efficacy, the vast majority of patients with HIV who developed invasive pneumococcal disease had a CD4 count <200 cells/microL [11].

B cell immunity, which is critical for protection against encapsulated organisms, is impaired in patients with late-stage acquired immunodeficiency syndrome (AIDS) [4,12]. Some in vitro data suggest that these defects in B cell immunity begin early in HIV infection and may be related to immune activation and the production of proinflammatory cytokines during untreated disease [4]. High levels of HIV ribonucleic acid (RNA) have also been associated with increased risk of pneumococcal disease [8,13,14].

Observational data suggest that other risk factors for invasive pneumococcal infection in patients with HIV include [5,8-10,15]:

●Cirrhosis

●Low serum albumin

●Heavy alcohol use

●Injection drug use

●Smoking

●Previous episodes of pneumonia

In contrast, receipt of ART and antibiotic prophylaxis (eg, trimethoprim-sulfamethoxazole), which is given for the prevention of pneumocystis infection in patients with advanced immunosuppression, protect against pneumococcal disease [9,13,15-17] (see "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics").

However, people with HIV may have an incomplete recovery of immune function relevant to pneumococcal disease despite the use of antiretroviral therapy and despite high CD4 T cell levels [18,19], since pneumococcal disease rates remain higher in individuals with HIV even in the ART era. Epidemiologic data on incidence specifically in individuals on ART with an undetectable viral load are lacking though [20,21]. Other co-occurring risk factors (eg, cigarette smoking) likely play a role as well.

AVAILABLE VACCINE FORMULATIONS — Five types of pneumococcal vaccine are available: the 23-valent polysaccharide vaccine (ie, PPSV23), a 10-valent and 13-valent conjugate vaccine (ie, PCV 10 and PCV13), which have replaced the 7-valent conjugate vaccine (PCV7), and the 15-valent and 20-valent conjugate vaccine (ie, PCV15 and PCV20), which were both approved by the US Food and Drug Administration in 2021. PCV10 is not available in the United States but is still used in Canada and other areas of the world.

The PCV13 vaccine extends coverage of the prior PCV7 vaccine by including antigens to six additional serotypes of pneumococcus, including the 19A serotype, which has increased in frequency in the United States since the introduction of PCV7 immunization in children [22,23]. Similarly, the PCV15 adds two additional serotypes (22F and 33F), and the PCV20 vaccine adds seven additional serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) that cause invasive disease. A full discussion of these vaccines and their use in persons without HIV is found elsewhere. (See "Pneumococcal vaccination in adults".)

EFFICACY AND IMMUNOGENICITY OF PNEUMOCOCCAL VACCINES — Pneumococcal immunization has been recommended for patients with HIV in resource-rich settings since the mid-1990s, based on the high incidence of invasive disease in this patient population [24]. The only clinical trials evaluating the efficacy of pneumococcal vaccine in patients with HIV have been conducted in resource-limited settings.

Polysaccharide vaccine — The sole clinical trial that examined the efficacy of polysaccharide vaccine was conducted in 1312 adults with HIV over three years of follow-up, starting in 1995 [25,26]. Participants were randomly assigned to one dose of polysaccharide vaccine or a placebo inoculation. Invasive pneumococcal disease with bacteremia occurred in only 25 persons (15 in the vaccine arm and 10 in the placebo arm; hazard ratio [HR] 1.47, 95% CI 0.7-3.3). Twenty-two isolates (88 percent) were of vaccine-specific serotypes (15 versus 7 events in the vaccine arm versus the placebo arm, respectively; HR 2.1, 95% CI 0.9-5.2). Unexpectedly, the number of cases of all-cause pneumonia was significantly higher in the intervention arm, although mortality did not differ.

Postimmunization titers doubled in only 40 percent of those assigned to the intervention arm. The authors concluded that although pneumococcal immunization with polysaccharide vaccine was well tolerated, the vaccine did not confer protection. Limitations of the trial included the following:

●The overall low number of cases of invasive pneumococcal disease

●The absence of antiretroviral therapy (ART), which probably contributed to the high rates of overall mortality seen in this trial (ie, 53 percent)

●Suboptimal vaccine immunogenicity since approximately 45 percent of the patients had advanced immunosuppression (eg, CD4 cell count <200 cells/microL)

Multiple observational studies have been performed in resource-rich settings to assess the effectiveness of pneumococcal polysaccharide vaccine against all cause pneumonia, pneumococcal pneumonia, and invasive pneumococcal disease (eg, bacteremia). A systematic review of these data suggests that most of the studies support a benefit of polysaccharide vaccine [2]. However, because of design flaws the available clinical evidence provides only moderate support for the efficacy of pneumococcal polysaccharide vaccine in adults with HIV [2].

Antibody responses to the 23-valent pneumococcal polysaccharide vaccine in patients with HIV are lower than those achieved in healthy subjects [27,28]. Rates of seroconversion are generally lower in patients with CD4 counts below 300 cells/microL [29-31], although patients on ART achieve a more durable antibody response than untreated patients, independent of the baseline CD4 cell count prior to immunization [32].

Conjugate vaccines — Studies have demonstrated immunogenicity of PCV among adults with HIV [11,33-37].

The immunogenicity and efficacy of PCV7 have been demonstrated in clinical trials, although the trials were conducted before the widespread use of ART. In one double-blind clinical trial conducted in Malawi, the efficacy of pneumococcal immunization for secondary prevention was evaluated among 496 patients who had been hospitalized with documented invasive pneumococcal disease; 88 percent also had underlying HIV, but only 13 percent of the patients with HIV were taking ART [11]. In the intervention arm, two doses of PCV7 were administered four weeks apart, starting one week after hospital discharge. Over a median follow-up of approximately 14 months, a lower number of episodes of pneumococcal disease (caused by vaccine serotypes or the 6A serotype) occurred in the vaccine group compared with the placebo group (5 versus 19) for an estimated overall vaccine efficacy of 74 percent among patients with HIV (95% CI 30-90 percent). There was no significant difference in all-cause mortality or mortality associated with pneumococcal disease between the intervention and placebo groups.

Studies have also demonstrated the immunogenicity of PCV13 [34,35]. In an open-labeled study in the United States of 329 adults with virally suppressed HIV, CD4 cell counts ≥200 cells/microL, and who had previously received at least one dose of the PPSV23, PCV13 elicited both anticapsular polysaccharide immunoglobulin G and opsonophagocytic antibody responses to each of the included serotypes [34]. Although efficacy of PCV13 in adults with HIV has not been proven, a retrospective study demonstrates an association between the introduction of PCV13 in 2012 and the declining incidence of invasive pneumococcal disease [38]. Data collected from 2008 to 2018 from the Active Bacterial Core surveillance platform demonstrated that the overall incidence of pneumococcal disease declined by 40.3 percent, and incidence of PCV-13-type invasive pneumococcal disease declined by 72.5 percent, though notably incidence in 2018 remained higher in people with HIV than people without HIV, 16.8 times higher overall, and 12.6 times higher in PCV-13-type disease. The authors noted that PCV-13 serotypes comprised 21.5 percent of disease in that year while PCV-15/non-PCV-13 and PCV-20/non-PCV-15 serotypes comprised 11.2 percent and 16.5 percent, respectively.

Studies have also evaluated immunogenicity of the 15-valent conjugate vaccine (PCV15) among adults with HIV. In a phase 3, multicenter, randomized, double-blind, active comparator-controlled study, serotype-specific opsonophagocytic activity titers and IgG concentration at 30 days postvaccination with PCV15 were elevated for all serotypes contained in the vaccine, with levels comparable to the PCV13 for the shared serotypes between the two vaccines [37]. In this study, all participants subsequently received the PPSV23.

There are no published trials evaluating the efficacy of the 20-valent conjugate vaccines in people living with HIV.

Prime boost effect — There are no head-to-head trials comparing polysaccharide vaccines and conjugate vaccines in patients with HIV. However, there are promising data regarding a prime-boost effect of PCV followed by PPSV23 on inducing and maintaining protective immunity. As an example, a systematic review and meta-analysis of 39 randomized trials and cohort studies demonstrated that compared with PPSV alone, a combination of PCV/PPSV yielded higher seroconversion rates (odds ratio 2.24, 95% CI 1.41-3.58); there was no significant difference in between PCV and PPSV23 alone [39].  

In another clinical trial, 212 French patients with HIV and CD4 cell counts of 200 to 500 cells/microL and plasma HIV RNA <50,000 copies/mL were randomly assigned to receive either PCV7 followed by a boost with 23-valent polysaccharide vaccine (PPSV23) four weeks later or PPSV23 alone at week 4 [33]. Patients who received the boosted regimen (PCV7 followed by PPSV23) had a greater frequency and breadth of serologic responses to Streptococcus pneumoniae polysaccharide antigens at eight weeks than patients who received PPSV alone. Early differences in IgG titers persisted at 24 weeks of follow-up with this prime-boost strategy. There were no data on clinical efficacy reported in this trial.

Preliminary data suggest that the use of adjuvants may be a promising tool to help improve overall vaccine immunogenicity [40].

VACCINE RECOMMENDATIONS

Vaccine administration — We agree with the CDC ACIP recommendations that all adults with HIV, regardless of CD4 cell count, should be vaccinated against Streptococcus pneumoniae [41]. The dosing schedule of pneumococcal vaccine depends on the patient’s immunization history and the availability of vaccines [42-45].

●Approach to individuals who have not received pneumococcal vaccines previously – For patients with HIV who have not previously received pneumococcal vaccines, the ACIP recommends PCV20 alone or PCV15 followed by PPSV23 ≥8 weeks later. We prefer to administer the PCV15/PPSV23 combination over PCV20 alone because there are data available on the immunogenicity of PCV15 in patients with HIV compared with PCV20 which has not been studied in patients with HIV. If PCV15 is unavailable, we administer PCV20 followed by PPSV23 to provide immunity against the three serotypes covered by PPSV23 that are not covered by PCV20 (figure 1). Additionally, the PCV-PPSV23 combination also provides potential immunogenic benefit from the “prime boost” effect. (See 'Prime boost effect' above.) Further discussion on the benefit of administering PPSV23 after PCV20 is discussed elsewhere. (See "Pneumococcal vaccination in adults", section on 'Approach to individuals at highest risk of pneumococcal disease' and "Pneumococcal vaccination in adults", section on 'Vaccine coverage against circulating serotypes'.)

●Approach to recipients of prior pneumococcal vaccines – The approach to individuals who have already received pneumococcal vaccines in the past depends on the specific vaccine they received (table 1 and table 2).

●Revaccination with PPSV23 – For patients who have received PCV20 alone, PCV20 in series with PPSV23, or PCV15 in series with PPSV23, no revaccinations are necessary [41]. For patients who received an older formulation of PCV (eg, PCV13) and PPSV23, we agree with the ACIP to administer a second dose of PPSV23 at least five years after the initial PPSV23 dose. If the second PPSV23 dose was administered before the age of 65, then an additional third dose of PPSV23 should be given after age 65, at least five years after the preceding PPSV23 dose. No more than three lifetime doses of PPSV23 are generally given.

All pneumococcal vaccines are administered as a 0.5 mL dose. PCV13, PCV15, and PCV20 should be given intramuscularly, whereas PPSV23 can be given either intramuscularly or subcutaneously. Intradermal administration can cause severe local reactions and should be avoided.

When to immunize — Administration of PCV is recommended at any CD4 cell count [43,45]. For patients with CD4 cell counts ≥200 cells/microL who have not yet received PPSV23, the PPSV23 dose can be given eight weeks after the PCV dose. For patients with CD4 cell counts <200 cells/microL who have not yet received PPSV23, we favor deferring administration of PPSV23 until the patient has achieved some degree of immune recovery (ie, a minimum CD4 count of 200 cells/microL) on antiretroviral therapy (ART), given the suboptimal immunogenicity of the vaccine at lower CD4 cell counts and the associated benefit of ART with antibody response [39]. (See 'Polysaccharide vaccine' above.)

This is consistent with the United States Centers for Disease Control and Prevention (CDC), National Institutes of Health, and the HIV Medicine Association recommendations, which note that although the PPSV23 can be given at least eight weeks after the PCV13, it may be preferable to defer administration of PPSV23 until the CD4 cell count exceeds 200 cell/microL [43]. On the other hand, the Infectious Diseases Society of America recommends administration of PPSV23 even if the CD4 cell count is less than 200 cells/microL but also consideration of revaccination for such patients after the CD4 cell count has increased above that threshold on ART [45].

For those who are not yet on ART but have a CD4 cell count ≥200 cells/microL, there does not appear to be a benefit to waiting until ART has been initiated before administering PPSV23 in an attempt to improve the immune response. In a trial of such patients, serotype specific immune responses were not different between those randomly assigned to receive PPSV23 at enrollment and those who received it six months or longer after ART initiation [46].

ADVERSE EVENTS — Polysaccharide vaccine and conjugate vaccines are all well tolerated. The major adverse event is soreness at the injection site. This is discussed in further detail elsewhere. (See "Pneumococcal vaccination in adults", section on 'Adverse effects'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in adults" and "Society guideline links: Immunizations in persons with HIV".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors − Pneumococcal pneumonia and meningitis are leading causes of morbidity and mortality among patients with HIV worldwide and treatment is complicated by the increasing incidence of drug-resistant pneumococcal strains. The most important risk factor for developing pneumococcal infections is the level of immunosuppression (eg, CD4 count <200 cells/microL). (See 'Epidemiology of pneumococcal disease' above.)

●Available vaccine formulations − Available pneumococcal vaccine formulations include the 23-valent polysaccharide vaccine (PPSV23), the 10-valent, 13-valent, 15-valent, and 20-valent conjugate vaccines ( PCV10, PCV13, PCV15, and PCV20). The numbers indicate the number of pneumococcal capsule types included in the vaccine, with each newer vaccine providing protection against a greater number of pneumococcal serotypes. (See 'Available vaccine formulations' above.)

●Immunogenicity and efficacy of pneumococcal vaccines

•Immunogenicity of pneumococcal vaccines is lower among patients with HIV compared with healthy participants, although patients with HIV taking antiretroviral therapy (ART) achieve higher vaccine-specific antibody titers than those who are not taking ART. (See 'Efficacy and immunogenicity of pneumococcal vaccines' above.)

•PCV7, PCV13, and PCV15 have all demonstrated immunogenicity in patients with HIV. There are no published data on the immunogenicity of the 20-valent conjugate vaccine in individuals with HIV. (See 'Conjugate vaccines' above.)

•“Prime-boost” effect refers to the hypothesis that immunogenicity of PPSV23 is boosted by prior administration of PCV. Although this phenomenon has not been convincingly established, it supports the choice of administering a combination PCV-PPSV23 regimen over PCV20 alone. (See 'Prime boost effect' above.)

●Vaccine recommendations − We recommend pneumococcal immunization in adults with HIV (Grade 1B).

•Approach to adults who have not received pneumococcal vaccines previously − We prefer to administer PCV15 followed by PPSV23 based on available immunogenicity data for PCV15 in adults with HIV. If PCV15 is not available, PCV20 is a reasonable substitute. We prefer a combination PCV-PPSV23 vaccine regimen to provide protection against serotypes present in PPSV23 that are absent from PCV15 and PCV20 (figure 1) and the potential “prime boost” effect. (See 'Vaccine recommendations' above.)

•Approach to recipients of previous pneumococcal vaccines − For recipients of previous pneumococcal vaccines, a suggested approach is outlined in the tables (table 1 and table 2). (See 'Vaccine recommendations' above.)

•Revaccination − For patients who have received PCV20 alone, PCV20 in series with PPSV23, or PCV15 in series with PPSV23, no revaccinations are necessary. For patients who received PCV13 and PPSV23, a second dose of PPSV23 should be given five years after an initial PPSV23 dose. If the second dose was administered prior to age 65, an additional single dose of PPSV23 should be given after age 65, at least five years after the preceding PPSV23 dose. No more than three lifetime doses of PPSV23 are generally given. (See 'Vaccine administration' above.)

●When to immunize − The 15-valent or 20-valent vaccine should be administered regardless of the CD4 cell count. The polysaccharide vaccine is more likely to be immunogenic when administered at a CD4 cell count greater than 200 cells/microL. (See 'When to immunize' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.