Although the World Health Organization has declared an end to the coronavirus disease 2019 (COVID-19) public health emergency, the prevalence of SARS-CoV-2 remains high (1). As of February 2, 2025, more than 770 million individuals worldwide have been infected, with over 7.08 million reported deaths (WHO COVID-19 Dashboard). The COVID-19 landscape is further complicated by acquired immunodeficiency syndrome (AIDS), a condition marked by profound immunodeficiency due to untreated human immunodeficiency virus (HIV) infection. People with HIV (PWH) experience a higher burden of non-HIV comorbidities, which predispose to more severe COVID-19, particularly in the setting of untreated HIV infection or low CD4⁺ T cell counts (2–4). Recent data also indicate that PWH have had a relative increase in mortality with COVID-19 compared with the general population (5).

Vaccination remains a cornerstone of COVID-19 control, and several vaccine platforms—mRNA (BNT162b2, mRNA-1273), adenoviral vector (ChAdOx1 nCoV-19, Ad26.COV2.S), and inactivated virus (BBIBP-CorV, CoronaVac)—were widely deployed during the pandemic. While numerous meta-analyses have examined primary vaccination outcomes in PWH, limited evidence exists regarding the immunogenicity and safety of COVID-19 booster doses in this population (6–9). Existing studies on primary vaccination show that PWH, across ethnic and geographic contexts, develop neutralizing antibodies and exhibit reduced COVID-19 risk post-vaccination (10). However, seroconversion rates remain lower in PWH compared to healthy controls (HC) (11). To maintain adequate protection, booster doses are recommended for immunocompromised individuals in many countries (12). Nonetheless, the magnitude and quality of humoral and T-cell responses to booster vaccination in PWH—particularly those with advanced immunosuppression—remain inadequately characterized.

Vaccine-induced protection depends not only on neutralizing antibodies but also on cellular immunity, particularly CD4+ T cell responses (13). CD4⁺ T cells, primary targets of HIV, are essential for orchestrating both humoral and cellular immunity. Regulatory T cells (Tregs) also contribute to immune modulation following vaccination (14). Diminished CD4⁺ T cell counts can impair neutralizing antibody production, lower seroconversion rates, and compromise overall vaccine efficacy.

This systematic review and meta-analysis evaluated the immunogenicity and safety of administering three or more COVID-19 vaccine doses to PWH. It compared seroconversion rates between PWH and HC, and assessed the association between neutralizing antibody levels and CD4⁺ T cell counts, along with other immune correlates. The findings offer critical insights for optimizing booster vaccination strategies in PWH.

This systematic review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (15) and was registered in PROSPERO (CRD42024605151).

The study selection process is summarized in Figure 1 . Of the 7,591 articles retrieved, 1,584 duplicates were removed. After screening titles and abstracts, 3,965 irrelevant studies and 1,737 reviews or meta-analyses were excluded. Full-text review excluded 207 animal studies, 40 studies involving only two vaccine doses, and four studies with unusable data. Ultimately, 54 articles were included in the meta-analysis (16–48) 23 of which conducted direct comparisons between PWH and HC.

Given the proven efficacy of vaccination in reducing infection risk and disease severity among PWH, enhancing vaccine coverage in this population is imperative (9). This meta-analysis included 54 studies, with 44 studies assessing seroconversion in 5,229 PWH. Additionally, 23 studies comparing PWH to HC after a third vaccine dose found no significant difference in seroconversion rates between the two groups. Subgroup analyses by vaccine type and geographic region revealed that exclusion of the highly biased Matveev study substantially reduced heterogeneity. Consistent with previous findings, mRNA vaccines produced the highest seroconversion rates for booster doses (11, 56). These results suggest that a third vaccine dose elicits a humoral immune response in PWH comparable to that in HC, enhancing antibody production, which has been demonstrated by others to correlate with reduced disease severity (57) and hospitalization (58).

A significant correlation exists between neutralizing antibody levels and both the quantity and proportion of CD4⁺ T cells (59, 60). CD4⁺ T cells (helper T lymphocytes) are central to anti-HIV immunity but are also the primary targets of HIV infection. Therefore, monitoring CD4⁺ T cells can help assess the extent of immune damage and determine the effectiveness of antiretroviral therapy (ART) (61). As such, CD4⁺ T cell quantification is essential for staging HIV infection and AIDS, as well as monitoring treatment response (62). In SARS-CoV-2 infection, CD4⁺ T cell responses are more prominent than those of CD8⁺ T cells. Notably, SARS-CoV-2–specific CD4⁺ T cells demonstrate the strongest association with reduced COVID-19 severity compared to antibody or CD8⁺ T cell responses (14). A meta-analysis of individuals receiving one to two doses of hepatitis B virus (HBV) vaccine found that PWH with CD4⁺ T cell counts below 500 cells/mm³ exhibited diminished seroconversion responses to hepatitis B virus, although response rates were generally consistent across studies (63). To assess seroconversion after a third vaccine dose, this study stratified PWH by CD4⁺ T cell count using the 200 cells/mm³ threshold. The antibody conversion rate was significantly higher in those with counts above 200 cells/mm³ compared to those below this threshold. Although subgroup analyses by vaccine type and geographic region did not explain the heterogeneity, further analysis identified individuals with CD4⁺ T cell counts <200 cells/mm³ as the main source of heterogeneity. This heterogeneity may also be influenced by HIV disease progression and ART status.

T helper 1 (Th1) and follicular helper T (Tfh) cells—differentiated subsets of CD4⁺ T cells—are critical for establishing long-term antiviral immunity (64). Upon differentiation, these cells activate phagocytes and cytotoxic CD8⁺ T cells (65), and support B cell maturation in germinal centers to produce high-affinity, long-lived antibodies (66). Accordingly, CD4⁺ and Tfh cells are considered key markers of durable, protective antibody responses (67). CD4⁺ T cells produce a broad array of cytokines, including TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-9, IL-10, IL-17, and IL-22. Th1 cells predominantly secrete TNF-α, IFN-γ, and IL-2, while Th2 cells produce IL-4, IL-5, IL-9, and IL-13. Th17 and regulatory T cells (Tregs) are sources of IL-17 and IL-10, respectively. Notably, IL-22 is highly expressed by mucosal CD4⁺ T cells specific to SARS-CoV-2 (14, 17, 29, 37, 41, 44, 51). Findings from included studies showed that in PWH, a third vaccine dose activated Th1, Treg, and Tfh cells and increased cytokine expression—including IFN-γ, IL-17, and IL-22 (17, 41). Both CD4⁺ and CD8⁺ T cells contributed to enhanced antibody responses, with CD4⁺ T cells showing a more pronounced role in SARS-CoV-2 immunity (29, 44, 49, 66, 68, 69).

This study also found no differences in the safety profile of COVID-19 booster vaccines between PWH and HC. Previous research suggests that PWH experience fewer adverse events after the second dose compared to the first (70–72). However, limited data exist on the safety of booster doses, and individuals who tolerate initial doses well may be more likely to receive boosters (73, 74). Our findings support the safety of booster vaccination in PWH and may help reduce vaccine hesitancy in this population.

To the best of our knowledge, this is the most comprehensive analysis of COVID-19 booster vaccine immunogenicity and safety in PWH. The study included all relevant literature published from January 1, 2020, to October 22, 2024, involving PWH who received ≥3 doses of a COVID-19 vaccine. These findings provide valuable evidence to address booster vaccine hesitancy among PWH.

Nonetheless, this study has limitations. Firstly, we did not evaluate the real-world effectiveness of booster doses in PWH due to a lack of original studies. Taking into account various factors, such as ART, previous COVID-19 infection, the timing of vaccination, and other viral infections, further research should be designed to explicitly evaluate the effectiveness of booster vaccination in this population. Secondly, although seroconversion indicates potential protection against SARS-CoV-2, it is not a definitive clinical endpoint, which would be better assessed by infection rates. However, few studies address this outcome. Lastly, substantial heterogeneity across studies—likely due to differences in study location, timing, and sample size—underscores the need for future research to validate these findings.

The findings of our research suggest that the humoral immune response elicited in PWH following administration of the COVID-19 booster vaccine is comparable to that observed in HC. The enhanced antibody response following the administration of a booster shot may similarly contribute to this protective effect. However, PWH with CD4⁺ T cell counts below 200 cells/mm³ continue to exhibit suboptimal antibody seroconversion despite receiving booster doses. These results underscore the importance of booster vaccination in PWH, particularly those with advanced immunosuppression, and suggest that optimizing booster regimens may improve immune outcomes in this population.