Immunogenicity of COVID-19 Vaccination in People Living with HIV: Progress and Challenges : Infectious Diseases & Immunity

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Immunogenicity of COVID-19 Vaccination in People Living with HIV: Progress and Challenges

Song, Jin-Wen1; Shen, Lili2; Wang, Fu-Sheng1,∗

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Infectious Diseases & Immunity 3(2):p 90-96, April 2023. | DOI: 10.1097/ID9.0000000000000073
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1. Introduction

Coronavirus disease 2019 (COVID-19), a highly contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a significant threat to public health and economies.[1] Severe acute respiratory syndrome coronavirus 2 vaccines are probably the safest and most effective approach to achieving sustained control of the COVID-19 pandemic. Therefore, many countries have launched massive COVID-19 vaccine campaigns. Various subtypes of COVID-19 vaccines developed using different platforms have been implemented for clinical use, including inactivated, mRNA, protein subunit, and adenovirus vector vaccines.[2] Some vaccines have been proven safe, immunogenic, and effective in protecting vaccinators from SARS-CoV-2 infection, COVID-19–associated hospitalization, or poor COVID-19 outcomes in large populations.[3–8] However, concerns about the immunogenicity and efficacy of SARS-CoV-2 vaccines have been raised in immunocompromised or vulnerable populations who are prone to develop severe COVID-19.

With more than 38 million patients are living with human immunodeficiency virus (HIV) globally, HIV infection remains a great challenge to public health.[9] Antiretroviral therapy (ART) can effectively suppress ongoing HIV replication and restore CD4 T-cell numbers, thereby improving the mortality and morbidity rates in people living with HIV (PLWH). However, immunological dysregulation persists, and many patients display persistent inflammation, immune activation, and exhaustion. In addition, other infections are more frequently observed in individuals with weakened immune systems during HIV infection. Although the prevalence of SARS-CoV-2 infection in PLWH was similar to the general population, a higher risk of severe COVID-19 has been reported in PLWH, especially in those with uncontrolled viremia and compromised CD4 T-cell count.[9] Thus, many countries and organizations recommend prioritizing PLWH for COVID-19 vaccination.[10] This review aimed to summarize the current progress in the immunogenicity and efficacy of different types of SARS-CoV-2 vaccines in PLWH and discuss the future challenges in controlling this pandemic in PLWH.

2. HIV-induced immune dysregulations

The hallmarks of HIV infection include the destruction of CD4 T cells, a reversed CD4/CD8 ratio, impaired mucosal integrity, chronic immune activation, and inflammation. The depletion of CD4 T cell has been witnessed in peripheral blood, gastrointestinal tract, and lymph nodes, and we have previously demonstrated that both apoptosis and pyroptosis contribute to the loss of CD4 T cell during HIV infection.[11] In addition, the impaired function of CD4 T cells has also been reported. For example, T follicular helper (Tfh) cells, as a subset of CD4 T cells, which have the critical role in promoting the proliferation, maturation, class switching, and antibody production of B cells via interleukin-21 secretion and receptor-ligand interactions, become dysfunctional in HIV infection.[12,13] During HIV infection, extensive follicular structure damage and loss of Tfh cells have been observed in lymph nodes, the critical tissue for adaptive immune responses.[14] In addition, HIV-induced inflammation results in collagen formation in the parafollicular T-cell zone, and lymph node fibrosis develops instead of the well-tuned fibroblastic reticular cell network, a structure supporting normal immune responses.[15] Furthermore, B-cell abnormalities have also been observed during HIV infection.[16] Collectively, impaired number and function of CD4 T cells, lymph node fibrosis, defective Tfh cells, and B-cell abnormalities might impair adaptive immune function and vaccine responses in PLWH.[17]

According to WHO global report, approximately 73% of PLWH have received ART. Effectively ART could promote the recovery of CD4 T cells and immune function in PLWH, especially in those treated during acute HIV infection. However, approximately 15% to 30% of patients do not achieve optimal CD4 T-cell recovery, which is termed as immunological nonresponders (INRs).[18–21] These patients have a higher risk of morbidity and mortality than those who achieve optimal CD4 T-cell recovery.[22] In addition, aberrant immune activation and inflammatory responses persist, despite successful ART.[23,24] Human immunodeficiency virus–induced immune activation and inflammation are the underlying causes of premature aging, which is closely associated with increased non-AIDS–related diseases, including diabetes, cardiovascular diseases, and others.[25] In addition, patients with some underlying comorbidities have an increased risk to develop severe COVID-19.[26] Thus, PLWH are more vulnerable to severe COVID-19 but may present with compromised response to routine vaccines.

3. SARS-CoV-2 coinfection in PLWH

Although no clinical evidence demonstrates the higher prevalence of COVID-19 or COVID-19 diagnosis rate in PLWH than in the general population,[9,27–30] more studies in large-scale population suggested that PLWH might have increased risk of COVID-19–related hospitalization or death than healthy individuals.[28,29,31–36] Residual inflammation and immune activation even after successful ART, as well as the high rate of comorbidities in PLWH, might result in poor COVID-19 outcomes. Furthermore, PLWH, especially those with unsuppressed viral load or low CD4 T-cell count, may exhibit prolonged viral shedding and worse COVID-19 outcomes.[31,32,36] Geretti et al.[33] described hospitalized COVID-19 patients at 207 centers across the United Kingdom, revealing that HIV infection was associated with the risk of day 28 mortality. Another study using the OpenSAFELY platform in the United Kingdom, including 27,480 PLWH, also indicated that PLWH had higher risk of COVID-19–associated death.[34] The National COVID Cohort Collaborative data, including 54 clinical sites in the United States, indicated that PLWH had increased COVID-19 mortality and hospitalization odds than people without HIV.[35] They also showed that PLWH with CD4 T cells less than 200 cells/μL were associated with poor COVID-19 outcomes, and suppressed HIV viral load on ART was associated with reduced hospitalization. Nomah et al.[37] also showed that PLWH with detectable viremia and chronic comorbidities were related to a higher risk of severe COVID-19. One study conducted in New York, including 2988 PLWH, revealed that PLWH experienced a higher rate of severe diseases requiring hospitalization than those without HIV diagnoses.[28] Spinelli et al.[38] reported that PLWH had 5.52 times higher odds of developing severe COVID-19. They found that neutralizing antibody levels and SARS-CoV-2 specific immunoglobulin G (IgG) concentration were lower in PLWH than in the HIV-negative population. These results raise the concern that PLWH may have a blunted serological immune response to natural SARS-CoV-2 infection or vaccination. More efforts should be made to ensure sufficient protection for PLWH.

4. COVID-19 vaccination in PLWH

An unprecedented speed of SARS-CoV-2 vaccines development has resulted from global collaboration and the great efforts made by research communities. Various SARS-CoV-2 vaccines have been developed using different platforms, including inactivated, mRNA, protein subunit, and adenovirus vector vaccines.[39] Several vaccines are safe and efficacious in clinical trials with large populations; however, the data on PLWH still need to be clarified. Previous studies have shown that PLWH demonstrated a lower magnitude or less durable humoral response after vaccination against hepatitis B, yellow fever, influenza, pneumococcus, and others.[40] These results further aggravate concerns regarding the efficacy of SARS-CoV-2 vaccines in PLWH. Although SARS-CoV-2 vaccines are proved to be well tolerated and safe in PLWH, immunogenicity of the SARS-CoV-2 vaccine varies, because of the different vaccine types, demographic differences of enrolled participants, or method used for humoral response detection. As neutralizing antibodies (NAbs) are now considered an essential correlate of protection,[41] several studies have measured SARS-CoV-2 NAbs using pseudovirus neutralization assay or surrogate virus neutralization test. Some studies have detected antibodies against the SARS-CoV-2 spike protein (spike) or SARS-CoV-2 spike protein receptor-binding domain (RBD). Here, we focused on the immunogenicity of different SARS-CoV-2 vaccines in PLWH [Table 1]. Because most studies of the following sections are conducted in PLWH who have achieved viral suppression with ART, PLWH are referred to virological suppressed individuals thereafter unless specified.

Table 1 - Studies of 2-dose SARS-CoV-2 vaccine in PLWH
Study Vaccine Numbers (PLWH vs. HC) Time Points After Second Vaccination Antibody Measuring Immunogenicity (PLWH vs. HC)
Response Rate (%) Titers
Netto et al. (2022) Brazil[42] CoronaVac 215 vs. 296 69 d NAb 71 vs. 84 46.2 (26.9–69.7) a vs. 60.8 (39.8–19.9) a
Anti-spike IgG 91 vs. 97 48.7 (26.6–88.2) a vs. 75.2 (50.3–112.0) a AU/mL
Balcells et al. (2022) Chile[43] CoronaVac 55 vs. 65 6 wks SARS-CoV-2 IgG 70.9 vs. 92.3 21.20 (15.98–28.13) a vs. 36.77(30.0–45.05) a RU/mL
NAb 45.5 vs. 83.1 28.72 (15.74–54.13) a vs. 51.21 (34.6–68.6) a
Ao et al. (2022) China[44] CoronaVac or BBIBP-CorV 139 vs. 120 40 d Anti-RBD IgG 87.1 vs. 99.2 134.2 (114.0–158.0) b vs. 317.5 (267.1–377.4) b
Anti-spike IgG NA 2 (1.51–2.85) b vs. 2.32 (1.79–3.25) b AU/mL
Han et al. (2022) China[45] CoronaVac or BBIBP-CorV 10 vs. 18 4 wks SARS-CoV-2 IgG 70 vs. 100 1.15 (0.26–5.01) b vs. 19 (16–23) b
NAb to D614G variant 80 vs. 100 43 (15–120) b vs. 165
NAb to delta variant 70 vs. 94.4 13 (8–22) b vs. 72
Liu et al. (2021) China[47] CoronaVac 55 vs. 21 5 wks Anti-RBD IgG NA 15.8 (10.4–23.3) a vs. 16 (11.3–23.2) a U/mL
Lv et al. (2022) China[48] CoronaVac or BBIBP-CorV 24 vs. 24 40 d NAb 79.17 vs. 87.50 NA
Feng et al. (2022) China[49] BBIBP-CorV 42 vs. 28 4 wks Anti-RBD IgG 57.1 vs. 92.9 NA
NAb 69 vs. 71.4
Heftdal et al. (2022) Denmark[53] BNT162b2 269 vs. 538 5 wks Anti-RBD IgG 100 vs. 99.6 20,442 (18,033–23,156) b vs. 25,171 (31,571–38,949) b AU/mL
Jedicke et al. (2021) Germany[54] BNT162b2 50 vs. 41 35 d Anti-spike IgG NA 246.2 (218.7) c vs. 502.5 (118.8) c RU/mL
Levy et al. (2021) Israel[55] BNT162b2 143 vs. 261 18 vs. 26 d Anti-RBD IgG 97 vs. 98.9 5.17 (4.84–5.53) b vs. 6.1 (5.8–6.4) b
NAb 97 vs. 98 449.0 (366.6–550.0) b vs. 482.8 (410.8–567.5) b
Bergman et al. (2021) Sweden[56] BNT162b2 78 vs. 79 35 d Anti-RBD IgG 98.7 vs. 100 NA
Tau et al. (2022) Israel[58] BNT162b2 136 vs. 61 135 ± 21 vs. 201 ± 9 d Anti-RBD IgG NA 118 (61.2–238.6) b vs. 101.4 (52.5–185) b BAU/mL
Lombardi et al. (2022) Italy[59] mRNA-1273 62 vs. 8 28 d NAb NA 1567 (789–3531) a vs. 2112 (719–8889) a
Spinelli et al. (2021) United States[60] BNT162b2 or mRNA-1273 100 vs. 100 35 d SARS-CoV-2 IgG 88 vs. 95 NA
NAb 76 vs. 88
Portillo et al. (2021) Switzerland[61] BNT162b2 or mRNA-1273 131 vs. 49 30 d Anti-RBD IgG NA 1303 (1076–1579) a vs. 1897 (1611–2232) a IU/mL
Madhi et al. (2021) South Africa[65] AZD1222 32 vs. 23 14 d Anti-spike IgG 93.8 vs. 95.7 453.1 (267.4–767.7) b vs. 504.9 (337.1–756.2) b
Anti-RBD IgG 87.5 vs. 95.7 347.8 (195.0–620.4) b vs. 364.2 (238.6–555.8) b
Frater et al. (2021) United Kingdom[66] AZD1222 49 vs. 47 28 d Anti-spike IgG NA 941 (531–1445) a vs. 631 (338–1037) a EUs
Madhi et al. (2022) South Africa[72] NVX-CoV2373 58 vs. 1216 14 d Anti-spike IgG 100 vs. 99.3 14,420.5 (10,603.0–19,612.3) b vs. 31,631.8 (29,712.6–33,675.1) b EU/mL
aData are expressed as median (Q1–Q3).
bData are expressed as GMT (95% CI).
cData are expressed as median (interquartile range).
PLWH: people living with HIV; HC: healthy control; PCDR: poor CD4 recovery; HCDR: high CD4 recover; Anti-RBD IgG: the IgG antibody against SARS-CoV-2 spike protein receptor-binding domain; Anti-spike IgG: the IgG antibody against SARS-CoV-2 spike protein; SARS-CoV-2 IgG: the IgG antibody against SARS-CoV-2; NAb: neutralizing antibody against wild-type SARS-CoV-2; AU: arbitrary unites; IU: international unites; BAU: binding antibody unites; EU: ELISA units; GMT: geometric mean titre; CI: confidence interval; NA: Not applicable.

4.1 Inactivated SARS-CoV-2 vaccine

Inactivated SARS-CoV-2 vaccines, including CoronaVac (Sinovac, Beijing, China) and BBIBP-CorV (Sinopharm, Beijing, China), are mainly used in low- and middle-income countries. A study from Brazil showed that after receiving 2 doses of CoronaVac, PLWH had lower NAb positivity and SARS-CoV-2 specific IgG antibody titers than participants with no known immunosuppression. In addition, PLWH with CD4 T-cell count less than 500 cells/μL had lower immunogenicity than PLWH with CD4 T-cell count greater than 500 cells/μL.[42] A study in Chile, which assessed the humoral responses to CoronaVac in immunocompromised patients (including 55 PLWH) and healthy controls, found lower NAb positivity and neutralizing activity in PLWH; however, the ELISpot assay showed that antigen-specific T cells were similar between groups.[43] Ao et al.[44] evaluated the antibody responses after 2-dose CoronaVac or BBIBP-CorV in 139 PLWH and 120 healthy participants. Compared with healthy participants, reduced anti-RBD IgG, antispike IgG, and frequency of RBD-specific memory B cells in PLWH were observed, especially those with CD4 T-cell count below 200 cells/μL. Moreover, Han et al.[45] found that NAb against D614G and delta variants elicited by 2-dose inactivated COVID-19 vaccine in PLWH are inferior to those in healthy controls, especially PLWH with CD4 T-cell count less than 350 cells/μL. In addition, one study assessed the immunogenicity of the third doses of CoronaVac in PLWH and found that the third dose significantly induced humoral immunity; however, NAb was still lower in the PLWH group than in healthy controls.[46] However, there are some studies reporting comparable humoral immune responses induced by the COVID-19 vaccine between PLWH and healthy controls. Liu et al.[47] found comparable anti-RBD IgG titers between 55 PLWH and 21 healthy controls after receiving 2 doses of CoronaVac; however, INR with CD4 T-cell count less than 350 cells/μL had lower antibody responses than immunological responders with CD4 T-cell count more than 350 cells/μL. One study enrolled PLWH, who received 2 doses of CoronaVac or BBIBP-CorV, found that PLWH displayed comparable NAb positivity but lower levels of NAb titers compared with healthy controls.[48] In contrast, Feng et al.[49] described similar antispike IgG, NAb, and spike specific T cells responses between PLWH and healthy controls after receiving two doses of the BBIBP-CorV vaccine. Interestingly, they found that 2-does inactivated vaccine induced lower humoral responses in PLWH with CD4/CD8 ratio less than 0.6 than in PLWH with CD4/CD8 ratio greater than 0.6. In addition, the reduced CD4 T-cell count after SARS-CoV-2 vaccination was observed, although no adverse clinical manifestations related to the loss of CD4 T cells were identified.[49] Furthermore, a case report also reported CD4 T-cell loss and increased viral load in an untreated HIV-infected patient after receiving 2-dose BBIBP-CorV vaccine.[50]

4.2 mRNA vaccine

mRNA has emerged as a promising platform for developing vaccines in recent years, and 2 vaccines against SARS-CoV-2, BNT162b, and mRNA-1273, were developed by Pfizer-BioNTech and Moderna, respectively. Ruddy et al.[51] reported that after the first dose of mRNA vaccination, 12 PLWH developed anti-RBD IgG, but 2 participants with CD4 T-cell count less than 200 cells/μL developed lower antibody levels. However, these 2 participants exhibited substantial boosting with the second dose.[52] A study conducted in Denmark assessed the antibody response to 2-dose BNT162b2 vaccine in 269 PLWH and 538 age-matched controls. They found reduced anti-RBD IgG in PLWH compared with healthy participants. In addition, CD4 nadir less than 200 cells/μL was tightly related to impaired humoral responses after 3 weeks but not 2 months after the first dose.[53] Consistently, 2 groups also showed that PLWH developed lower anti-RBD IgG than controls after receiving 2-dose BNT162b2 vaccine.[54,55] In addition, Levy et al.[55] also observed a decline in CD4 T-cell count, as described in inactivated SARS-CoV-2 vaccines.[49] In contrast, Bergman et al.[56] and Woldemeskel et al.[57] described comparable anti-RBD IgG levels between PLWH and controls after receiving 2-dose BNT162b2 vaccine. Although Tau et al.[58] also found comparable humoral response between PLWH and healthcare workers after BNT162b2 vaccination, they noted that the anti-RBD IgG was lower in PLWH whose CD4 T cell was less than 300 cells/μL. Other studies also evaluate the immunogenicity of mRNA-1273 vaccine in PLWH. One study conducted in Italy compared anti-RBD IgG and NAbs after 2-dose of mRNA-1273 vaccine in 71 PLWH and 10 controls found comparable humoral response levels.[59] Moreover, 2 studies reported that PLWH receiving 2 doses of mRNA1273 or BNT162b2 vaccine mounted lower RBD IgG or NAbs than the control,[60,61] especially patients with low CD4 T-cell count or individuals administrated with BNT162b2 vaccine.[60] Although 2-dose mRNA vaccine elicit a stronger antibody response than 2-dose inactivated virus vaccine[62] and robust immunogenicity was observed in most PLWH mentioned previously, one case reported that one HIV-infected individual with extremely low CD4 T-cell count (CD4 = 20 cells/μL) and unsuppressed viremia failed to achieve seroconversion after 2-dose BNT162b2 vaccination.[63] Furthermore, one study reported that mRNA-1273 vaccination induced a transient increase in nonsuppressible viremia in an HIV-infected individual with previously sustained viral controls.[64]

4.3 Adenovirus vector vaccine

The safety and efficacy of adenovirus vector vaccines, including AZD1222 (ChAdOx1 nCoV-19) and Ad26.CoV2.S, developed by AstraZeneca and Janssen, respectively, have been demonstrated in large populations. AZD1222 used a replication-defective chimpanzee adenovirus vector while Ad26.CoV2.S used a recombinant human-based adenovirus vector. A phase 1B/2A clinical trial conducted in South Africa demonstrated similar antispike IgG, anti-RBD IgG, and NAb responses in PLWH and healthy individuals after administration of prime and booster doses of AZD1222 vaccine.[65] An UK cohort also found no difference in the magnitude and persistence of SARS-CoV-2 spike-specific humoral and cellular responses after the 2-dose AZD1222 vaccine.[66] Khan et al.[67] showed that a single dose of Ad26.CoV2.S vaccine elicited comparable neutralizing antibodies to the delta variant between PLWH and healthy individuals. A study comparing humoral responses to different vaccine regimens, including 2 doses of an mRNA or AZD1222, or heterologous (AZD1222-mRNA) vaccines, found that HIV infection was not significantly related to the magnitude of anti-RBD IgG or NAb titers after multivariable adjustment. Lower humoral responses were observed in people with older age, higher chronic disease burden, and dual AZD1222 vaccination regimens.[68] The COVICS study assessed the antibody response to 2 doses of an mRNA vaccine or AZD1222 or a single dose of Ad26.CoV2.S vaccine in healthy controls and immunocompromised individuals with 94 PLWH included, demonstrating that the seropositivity was lower in PLWH than in healthy participants, and PLWH with CD4 count less than 200 cells/μL were related to a lower seropositivity.[69] In addition, a German cohort, which included 665 PLWH receiving 2-dose mRNA vaccine, 2-dose AZD1222, heterogeneous (one AZD1222 plus one mRNA vaccine), or a single dose of Ad26.CoV2.S vaccine, found that a vaccination regimen containing mRNA vaccine, female, and a higher CD4 T-cell count was related to higher concentrations of antibodies against SARS-CoV-2 in PLWH.[70]

4.4 Protein subunit vaccine

The spike protein and its antigenic fragments are prime targets for the institution of the SARS-CoV-2 subunit vaccine. NVX-CoV2373 (Novavax) is a nanoparticle-based protein subunit vaccine using Matrix-M as an adjuvant. One study evaluated the efficacy of the NVX-CoV2373 vaccine against the B.1.351 variant. It showed that the efficacy of 2 doses of the NVX-CoV2373 vaccine was 49.4%, and 60.1% when PLWH were excluded from the analysis.[71] However, because of the limited number of PLWH enrolled in this study, and the trial was unpowered to detect efficacy in PLWH. Later, a phase 2A/2B clinical trial that evaluated the immunogenicity of 2-dose NVX-CoV2373 vaccine in PLWH revealed that PLWH had lower antispike IgG titers than healthy individuals after 2 weeks since receiving the second vaccination, but the seroconversion rates was similar.[72] Further studies may be required to assess the immunogenicity of the SARS-CoV-2 subunit vaccine in PLWH with lower CD4 T-cell count levels.

In general, PLWH mount comparable or lower immune response after receiving the COVID-19 vaccine, but PLWH with low CD4 T-cell count displayed relatively poor immune response than people with normal CD4 T-cell count.

5. Challenges and perspective

Massive vaccination is recognized as one of the most effective methods for controlling the COVID-19 pandemic. The safety and efficacy of various SARS-CoV-2 vaccines have been proven in clinical trials with general populations. However, the efficacy of SARS-CoV-2 vaccines in preventing symptomatic cases or severe illness in PLWH is still limited and should be evaluated in a large cohort of PLWH. Although data are still conflicting on the magnitude of the humoral response elicited by the COVID-19 vaccine in PLWH, these studies still support vaccination as a principal COVID-19 prevention strategy among PLWH. These COVID-19 vaccines mentioned previously are applicable to PLWH, and they are generally safe and no serious adverse reactions were observed, but different types of COVID-19 vaccinations might provide different level of protection in PLWH. In the perspective of immunogenicity-induced COVID-19 vaccines, mRNA vaccine can elicit stronger immune responses and may provide higher rate of protection against COVID-19.[73] In addition, long-term follow-up studies should be conducted to assess the durability of the humoral and cellular responses.

People living with HIV represent a distinct group of individuals with immunosuppressed conditions. Although ART can promote the recovery of immune functions in PLWH, especially in those treated during the acute HIV infection, many patients have not received ART or achieved optimal CD4 T-cell recovery after ART. The chances of developing severe COVID-19 diseases are higher in these PLWH with unsuppressed viral load or low CD4 T-cell count. Although COVID-19 vaccination is expected to reduce this risk, some studies have demonstrated a relatively lower humoral response in patients with lower CD4 T-cell count, and one case with uncontrolled viremia even failed to seroconvert after 2-dose BNT162b2 vaccination.[63] Thus, future studies need to enroll PLWH with uncontrolled viremia or low CD4 T-cell count to evaluate their immune responses to SARS-CoV-2 vaccines.

The emergence of SARS-CoV-2 variants poses an increased risk to global public health. Therefore, it is vital to evaluate the neutralizing antibody response against emerging SARS-CoV-2 variants. However, commonly used SARS-CoV-2 vaccines use the inactivated SARS-CoV-2 ancestral strain or the original sequence of spike protein. The neutralizing antibody response to variants, especially omicron, was significantly lower or even absent, although they retained T-cell immunity to the omicron variant.[74,75] Booster vaccination can only partially restore antibodies to neutralize the omicron variant.[75] Whether the current vaccine is protective against variants of SARS-CoV-2 in PLWH remains to be elucidated, and further studies should evaluate the cross-neutralization ability of antibodies to address various concerns. In addition, additional variant-specific vaccines may be needed to boost the immune response to emerging variants. Therefore, prioritizing COVID-19 booster vaccines in PLWH is still needed; however, vaccination strategies must be thoroughly considered. Moreover, prolonged viral shedding has been described in persons with advanced HIV disease in South Africa[32,76] and other immunosuppressed patients,[31,77] and SARS-CoV-2 can keep multiplying and piling up mutations. However, many HIV-infected individuals living in sub-Saharan Africa have not received ART treatment and have a weaken immune system.[78] The prolonged viral shedding may eventually promote the emergence of new SARS-CoV-2 variants. Thus, it is imperative to allocate COVID-19 vaccines to Africa and initiate ART for PLWH with uncontrolled HIV viremia.

In addition, during the vaccination process, clinical parameters, including viremia and CD4 count, should be continually monitored, and PLWH should continue to receive suppressive ART. Some studies have shown a decline in CD4 T cells and a transient increase in viral load during COVID-19 vaccination,[49,55] although no other adverse clinical outcomes were observed. In addition, an increase in HIV viral load was reported in PLWH receiving vaccinations for influenza,[79,80]Streptococcus pneumoniae,[81] and hepatitis B.[82] Furthermore, the increase of cell-associated HIV RNA has also been observed,[83] but it is still not clear whether the vaccination will impact HIV reservoir size.

In summary, the safety and immunogenicity of SARS-CoV-2 vaccines are well documented. However, future vaccination designs should improve immunogenicity in PLWH and consider the emerging variants to provide clinical protection for these patients. In addition, ART is vital for those with uncontrolled HIV viremia not only to prevent further destruction of CD4 T cells and restore immune functions but also to improve the immunogenicity of COVID-19 vaccines and lower the rate of emergence of a new variant.


This work was supported by the National Natural Science Foundation of China (No. 82101837), the Beijing Natural Science Foundation (No. 7222171), and Emergency Key Program of Guangzhou Laboratory (EKPG21-30-4).

Author Contributions

Jin-Wen Song and Fu-Sheng Wang conceived and designed the review. Jin-Wen Song and Lili Shen wrote the draft manuscript. Fu-Sheng Wang and Jin-Wen Song critically revised the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest


Editor note: Fu-Sheng Wang is the editor of Infectious Diseases & Immunity. The article was subject to the journal’s standard procedures, with peer review handled independently by this editor and his research group.


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HIV; SARS-CoV-2; Vaccine; Immunogenicity; Neutralizing antibody; ART

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