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. 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. 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. 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. Thus, many countries and organizations recommend prioritizing PLWH for COVID-19 vaccination. 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. 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. 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. Furthermore, B-cell abnormalities have also been observed during HIV infection. 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.
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. 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. In addition, patients with some underlying comorbidities have an increased risk to develop severe COVID-19. 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. 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. 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. 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. 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. Spinelli et al. 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. 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. 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, 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
||Numbers (PLWH vs. HC)
||Time Points After Second Vaccination
||Immunogenicity (PLWH vs. HC)
|Response Rate (%)
|Netto et al. (2022) Brazil
||215 vs. 296
||71 vs. 84
a vs. 60.8 (39.8–19.9)
||91 vs. 97
a vs. 75.2 (50.3–112.0)
|Balcells et al. (2022) Chile
||55 vs. 65
||70.9 vs. 92.3
a vs. 36.77(30.0–45.05)
||45.5 vs. 83.1
a vs. 51.21 (34.6–68.6)
|Ao et al. (2022) China
||CoronaVac or BBIBP-CorV
||139 vs. 120
||87.1 vs. 99.2
b vs. 317.5 (267.1–377.4)
b vs. 2.32 (1.79–3.25)
|Han et al. (2022) China
||CoronaVac or BBIBP-CorV
||10 vs. 18
||70 vs. 100
b vs. 19 (16–23)
|NAb to D614G variant
||80 vs. 100
b vs. 165
|NAb to delta variant
||70 vs. 94.4
b vs. 72
|Liu et al. (2021) China
||55 vs. 21
a vs. 16 (11.3–23.2)
|Lv et al. (2022) China
||CoronaVac or BBIBP-CorV
||24 vs. 24
||79.17 vs. 87.50
|Feng et al. (2022) China
||42 vs. 28
||57.1 vs. 92.9
||69 vs. 71.4
|Heftdal et al. (2022) Denmark
||269 vs. 538
||100 vs. 99.6
b vs. 25,171 (31,571–38,949)
|Jedicke et al. (2021) Germany
||50 vs. 41
c vs. 502.5 (118.8)
|Levy et al. (2021) Israel
||143 vs. 261
||18 vs. 26 d
||97 vs. 98.9
b vs. 6.1 (5.8–6.4)
||97 vs. 98
b vs. 482.8 (410.8–567.5)
|Bergman et al. (2021) Sweden
||78 vs. 79
||98.7 vs. 100
|Tau et al. (2022) Israel
||136 vs. 61
||135 ± 21 vs. 201 ± 9 d
b vs. 101.4 (52.5–185)
|Lombardi et al. (2022) Italy
||62 vs. 8
a vs. 2112 (719–8889)
|Spinelli et al. (2021) United States
||BNT162b2 or mRNA-1273
||100 vs. 100
||88 vs. 95
||76 vs. 88
|Portillo et al. (2021) Switzerland
||BNT162b2 or mRNA-1273
||131 vs. 49
a vs. 1897 (1611–2232)
|Madhi et al. (2021) South Africa
||32 vs. 23
||93.8 vs. 95.7
b vs. 504.9 (337.1–756.2)
||87.5 vs. 95.7
b vs. 364.2 (238.6–555.8)
|Frater et al. (2021) United Kingdom
||49 vs. 47
a vs. 631 (338–1037)
|Madhi et al. (2022) South Africa
||58 vs. 1216
||100 vs. 99.3
b vs. 31,631.8 (29,712.6–33,675.1)
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. 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. Ao et al. 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. 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. However, there are some studies reporting comparable humoral immune responses induced by the COVID-19 vaccine between PLWH and healthy controls. Liu et al. 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. In contrast, Feng et al. 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. 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.
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. 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. 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. 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. also observed a decline in CD4 T-cell count, as described in inactivated SARS-CoV-2 vaccines. In contrast, Bergman et al. and Woldemeskel et al. described comparable anti-RBD IgG levels between PLWH and controls after receiving 2-dose BNT162b2 vaccine. Although Tau et al. 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. 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. Although 2-dose mRNA vaccine elicit a stronger antibody response than 2-dose inactivated virus vaccine 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. 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.
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. 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. Khan et al. 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. 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. 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.
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. 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. 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. 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. 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. 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. 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, and hepatitis B. Furthermore, the increase of cell-associated HIV RNA has also been observed, 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).
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.
1. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579(7798):270–273. doi:10.1038/s41586-020-2012-7.
2. Shin MD, Shukla S, Chung YH, et al. COVID-19 vaccine
development and a potential nanomaterial path forward. Nat Nanotechnol 2020;15(8):646–655. doi:10.1038/s41565-020-0737-y.
3. Tanriover MD, Doganay HL, Akova M, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine
(CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet 2021;398(10296):213–222. doi:10.1016/S0140-6736(21)01429-X.
4. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine
. N Engl J Med 2020;383(27):2603–2615. doi:10.1056/NEJMoa2034577.
5. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine
. N Engl J Med 2021;384(5):403–416. doi:10.1056/NEJMoa2035389.
6. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine
(AZD1222) against SARS-CoV-2
: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397(10269):99–111. doi:10.1016/S0140-6736(20)32661-1.
7. Sadoff J, Gray G, Vandebosch A, et al. Safety and efficacy of single-dose Ad26.COV2.S vaccine
against Covid-19. N Engl J Med 2021;384(23):2187–2201. doi:10.1056/NEJMoa2101544.
8. Heath PT, Galiza EP, Baxter DN, et al. Safety and efficacy of NVX-CoV2373 Covid-19 vaccine
. N Engl J Med 2021;385(13):1172–1183. doi:10.1056/NEJMoa2107659.
9. Ambrosioni J, Blanco JL, Reyes-Uruena JM, et al. Overview of SARS-CoV-2
infection in adults living with HIV
. Lancet HIV
TL. Prioritise people with HIV
for COVID-19 vaccination. Lancet HIV
11. Zhang C, Song JW, Huang HH, et al. NLRP3 inflammasome induces CD4+
T cell loss in chronically HIV
-1-infected patients. J Clin Invest 2021;131(6):e138861. doi:10.1172/JCI138861.
12. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011;29:621–663. doi:10.1146/annurev-immunol-031210-101400.
13. Miles B, Miller SM, Connick E. CD4 T follicular helper and regulatory cell dynamics and function in HIV
infection. Front Immunol 2016;7:659. doi:10.3389/fimmu.2016.00659.
14. Xu H, Wang X, Malam N, et al. Persistent simian immunodeficiency virus infection causes ultimate depletion of follicular Th cells in AIDS. J Immunol 2015;195(9):4351–4357. doi:10.4049/jimmunol.1501273.
15. Zeng M, Southern PJ, Reilly CS, et al. Lymphoid tissue damage in HIV
-1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog 2012;8(1):e1002437. doi:10.1371/journal.ppat.1002437.
16. Moir S, Fauci AS. B-cell responses to HIV
infection. Immunol Rev 2017;275(1):33–48. doi:10.1111/imr.12502.
17. Kityo C, Makamdop KN, Rothenberger M, et al. Lymphoid tissue fibrosis is associated with impaired vaccine
responses. J Clin Invest 2018;128(7):2763–2773. doi:10.1172/JCI97377.
18. Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+
cell count restoration in HIV
-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 2009;48(6):787–794. doi:10.1086/597093.
19. Darraj M, Shafer LA, Chan S, et al. Rapid CD4 decline prior to antiretroviral therapy predicts subsequent failure to reconstitute despite HIV
viral suppression. J Infect Public Health 2018;11(2):265–269. doi:10.1016/j.jiph.2017.08.001.
20. Lederman MM, Calabrese L, Funderburg NT, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis 2011;204(8):1217–1226. doi:10.1093/infdis/jir507.
21. Rb-Silva R, Goios A, Kelly C, et al. Definition of immunological nonresponse to antiretroviral therapy: a systematic review. J Acquir Immune Defic Syndr 2019;82(5):452–461. doi:10.1097/QAI.0000000000002157.
22. Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV
-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis 2014;58(9):1312–1321. doi:10.1093/cid/ciu038.
23. Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV
-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A 2014;111(6):2307–2312. doi:10.1073/pnas.1318249111.
24. Lorenzo-Redondo R, Fryer HR, Bedford T, et al. Persistent HIV
-1 replication maintains the tissue reservoir during therapy. Nature 2016;530(7588):51–56. doi:10.1038/nature16933.
25. Deeks SG. HIV
infection, inflammation, immunosenescence, and aging. Annu Rev Med 2011;62:141–155. doi:10.1146/annurev-med-042909-093756.
26. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19–related death using OpenSAFELY. Nature 2020;584(7821):430–436. doi:10.1038/s41586-020-2521-4.
27. Cooper TJ, Woodward BL, Alom S, et al. Coronavirus disease 2019 (COVID-19) outcomes in HIV
/AIDS patients: a systematic review. HIV
Med 2020;21(9):567–577. doi:10.1111/hiv
28. Tesoriero JM, Swain CE, Pierce JL, et al. COVID-19 outcomes among persons living with or without diagnosed HIV
infection in New York state. JAMA Netw Open 2021;4(2):e2037069. doi:10.1001/jamanetworkopen.2020.37069.
29. Chang JJ, Bruxvoort K, Chen LH, et al. Brief report: COVID-19 testing, characteristics, and outcomes among people living with HIV
in an integrated health system. J Acquir Immune Defic Syndr 2021;88(1):1–5. doi:10.1097/QAI.0000000000002715.
30. Tang ME, Gaufin T, Anson R, et al. People with HIV
have a higher risk of COVID-19 diagnosis but similar outcomes to the general population. HIV
Med 2022. doi:10.1111/hiv
.13312. Online ahead of print.
31. Choi B, Choudhary MC, Regan J, et al. Persistence and evolution of SARS-CoV-2
in an immunocompromised host. N Engl J Med 2020;383(23):2291–2293. doi:10.1056/NEJMc2031364.
32. Hoffman SA, Costales C, Sahoo MK, et al. SARS-CoV-2
neutralization resistance mutations in patient with HIV
/AIDS, California, USA. Emerg Infect Dis 2021;27(10):2720–2723. doi:10.3201/eid2710.211461.
33. Geretti AM, Stockdale AJ, Kelly SH, et al. Outcomes of coronavirus disease 2019 (COVID-19) related hospitalization among people with human immunodeficiency virus (HIV
) in the ISARIC World Health Organization (WHO) clinical characterization protocol (UK): a prospective observational study. Clin Infect Dis 2021;73(7):e2095–106. doi:10.1093/cid/ciaa1605.
34. Bhaskaran K, Rentsch CT, MacKenna B, et al. HIV
infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform. Lancet HIV
35. Yang X, Sun J, Patel RC, et al. Associations between HIV
infection and clinical spectrum of COVID-19: a population level analysis based on US National COVID Cohort Collaborative (N3C) data. Lancet HIV
36. Dandachi D, Geiger G, Montgomery MW, et al. Characteristics, comorbidities, and outcomes in a multicenter registry of patients with human immunodeficiency virus and coronavirus disease 2019. Clin Infect Dis 2021;73(7):e1964–72. doi:10.1093/cid/ciaa1339.
37. Nomah DK, Reyes-Uruena J, Diaz Y, et al. Sociodemographic, clinical, and immunological factors associated with SARS-CoV-2
diagnosis and severe COVID-19 outcomes in people living with HIV
: a retrospective cohort study. Lancet HIV
38. Spinelli MA, Lynch KL, Yun C, et al. SARS-CoV-2
seroprevalence, and IgG concentration and pseudovirus neutralising antibody titres after infection, compared by HIV
status: a matched case-control observational study. Lancet HIV
39. Dong Y, Dai T, Wei Y, et al. A systematic review of SARS-CoV-2 vaccine
candidates. Signal Transduct Target Ther 2020;5(1):237. doi:10.1038/s41392-020-00352-y.
40. El Chaer F, El Sahly HM. Vaccination in the adult patient infected with HIV
: a review of vaccine
efficacy and immunogenicity
. Am J Med 2019;132(4):437–446. doi:10.1016/j.amjmed.2018.12.011.
41. Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody
levels are highly predictive of immune protection from symptomatic SARS-CoV-2
infection. Nat Med 2021;27(7):1205–1211. doi:10.1038/s41591-021-01377-8.
42. Netto LC, Ibrahim KY, Picone CM, et al. Safety and immunogenicity
of CoronaVac in people living with HIV
: a prospective cohort study. Lancet HIV
43. Balcells ME, Le Corre N, Duran J, et al. Reduced immune response to inactivated severe acute respiratory syndrome coronavirus 2 vaccine
in a cohort of immunocompromised patients in Chile. Clin Infect Dis 2022;75(1):e594–e602. doi:10.1093/cid/ciac167.
44. Ao L, Lu T, Cao Y, et al. Safety and immunogenicity
of inactivated SARS-CoV-2
vaccines in people living with HIV
. Emerg Microbes Infect 2022;11(1):1126–1134. doi:10.1080/22221751.2022.2059401.
45. Han X, Yu X, Han Y, et al. Safety and immunogenicity
of inactivated COVID-19 vaccines among people living with HIV
in China. Infect Drug Resist 2022;15:2091–2100. doi:10.2147/IDR.S353127.
46. Tan Y, Zou S, Ming F, et al. Early efficacy and safety of the third dose inactivated COVID-19 vaccine
among people living with HIV
. J Acquir Immune Defic Syndr 2022;90(3):e1–e3. doi:10.1097/QAI.0000000000002953.
47. Liu Y, Han J, Li X, et al. COVID-19 vaccination in people living with HIV
(PLWH) in China: a cross sectional study of vaccine
hesitancy, safety, and immunogenicity
48. Lv Z, Li Q, Feng Z, et al. Inactivated SARS-CoV-2
vaccines elicit immunogenicity
and T-cell responses in people living with HIV
. Int Immunopharmacol 2022;102:108383. doi:10.1016/j.intimp.2021.108383.
49. Feng Y, Zhang Y, He Z, et al. Immunogenicity
of an inactivated SARS-CoV-2 vaccine
in people living with HIV
-1: a non-randomized cohort study. EClinicalMedicine 2022;43:101226. doi:10.1016/j.eclinm.2021.101226.
50. Gong C, Song X, Li X, et al. Immunological changes after COVID-19 vaccination in an HIV
-positive patient. Int J Infect Dis 2021;117:230–232. doi:10.1016/j.ijid.2021.08.039.
51. Ruddy JA, Boyarsky BJ, Werbel WA, et al. Safety and antibody response to the first dose of severe acute respiratory syndrome coronavirus 2 messenger RNA vaccine
in persons with HIV
. AIDS 2021;35(11):1872–1874. doi:10.1097/QAD.0000000000002945.
52. Ruddy JA, Boyarsky BJ, Bailey JR, et al. Safety and antibody response to two-dose SARS-CoV-2
messenger RNA vaccination in persons with HIV
. AIDS 2021;35(14):2399–2401. doi:10.1097/QAD.0000000000003017.
53. Heftdal LD, Knudsen AD, Hamm SR, et al. Humoral response to two doses of BNT162b2 vaccination in people with HIV
. J Intern Med 2021;291(4):513–518. doi:10.1111/joim.13419.
54. Jedicke N, Stankov MV, Cossmann A, et al. Humoral immune response following prime and boost BNT162b2 vaccination in people living with HIV
on antiretroviral therapy. HIV
Med 2021;23(5):558–563. doi:10.1111/hiv
55. Levy I, Wieder-Finesod A, Litchevsky V, et al. Immunogenicity
and safety of the BNT162b2 mRNA COVID-19 vaccine
in people living with HIV
-1. Clin Microbiol Infect 2021;27(12):1851–1855. doi:10.1016/j.cmi.2021.07.031.
56. Bergman P, Blennow O, Hansson L, et al. Safety and efficacy of the mRNA BNT162b2 vaccine
in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine 2021;74:103705. doi:10.1016/j.ebiom.2021.103705.
57. Woldemeskel BA, Karaba AH, Garliss CC, et al. The BNT162b2 mRNA vaccine
elicits robust humoral and cellular immune responses in people living with HIV
. Clin Infect Dis 2021;74(7):1268–1270. doi:10.1093/cid/ciab648.
58. Tau L, Turner D, Adler A, et al. SARS-CoV-2
humoral and cellular immune responses of patients with HIV
after vaccination with BNT162b2 mRNA COVID-19 vaccine
in the Tel-Aviv Medical Center. Open Forum Infect Dis 2022;9(4):ofac089. doi:10.1093/ofid/ofac089.
59. Lombardi A, Butta GM, Donnici L, et al. Anti-spike antibodies and neutralising antibody activity in people living with HIV
vaccinated with COVID-19 mRNA-1273 vaccine
: a prospective single-Centre cohort study. Lancet Reg Health Eur 2022;13:100287. doi:10.1016/j.lanepe.2021.100287.
60. Spinelli MA, Peluso MJ, Lynch KL, et al. Differences in post-mRNA vaccination severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2
) immunoglobulin G (IgG) concentrations and surrogate virus neutralization test response by human immunodeficiency virus (HIV
) status and type of vaccine
: a matched case-control observational study. Clin Infect Dis 2021;75(1):e916–e919. doi:10.1093/cid/ciab1009.
61. Portillo V, Fedeli C, Ustero Alonso P, et al. Impact on HIV
-1 RNA levels and antibody responses following SARS-CoV-2
vaccination in HIV
-infected individuals. Front Immunol 2021;12:820126. doi:10.3389/fimmu.2021.820126.
62. Lim WW, Mak L, Leung GM, et al. Comparative immunogenicity
of mRNA and inactivated vaccines against COVID-19. Lancet Microbe 2021;2(9):e423. doi:10.1016/S2666-5247(21)00177-4.
63. Touizer E, Alrubayyi A, Rees-Spear C, et al. Failure to seroconvert after two doses of BNT162b2 SARS-CoV-2 vaccine
in a patient with uncontrolled HIV
. Lancet HIV
64. Bozzi G, Lombardi A, Ludovisi S, et al. Transient increase in plasma HIV
RNA after COVID-19 vaccination with mRNA-1272. Int J Infect Dis 2021;113:125–126. doi:10.1016/j.ijid.2021.10.021.
65. Madhi SA, Koen AL, Izu A, et al. Safety and immunogenicity
of the ChAdOx1 nCoV-19 (AZD1222) vaccine
in people living with and without HIV
in South Africa: an interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial. Lancet HIV
66. Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity
of the ChAdOx1 nCoV-19 (AZD1222) vaccine
infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV
67. Khan K, Lustig G, Bernstein M, et al. Immunogenicity
of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2
) infection and Ad26.CoV2.S vaccination in people living with human immunodeficiency virus (HIV
). Clin Infect Dis 2022;75(1):e857–e864. doi:10.1093/cid/ciab1008.
68. Brumme ZL, Mwimanzi F, Lapointe HR, et al. Humoral immune responses to COVID-19 vaccination in people living with HIV
receiving suppressive antiretroviral therapy. NPJ Vaccines 2022;7(1):28. doi:10.1038/s41541-022-00452-6.
69. Haidar G, Agha M, Bilderback A, et al. Prospective evaluation of coronavirus disease 2019 (COVID-19) vaccine
responses across a broad spectrum of immunocompromising conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS). Clin Infect Dis 2022;75(1):e630–644. doi:10.1093/cid/ciac103.
70. Noe S, Ochana N, Wiese C, et al. Humoral response to SARS-CoV-2
vaccines in people living with HIV
. Infection 2021;50(3):617–623. doi:10.1007/s15010-021-01721-7.
71. Shinde V, Bhikha S, Hoosain Z, et al. Efficacy of NVX-CoV2373 Covid-19 vaccine
against the B.1.351 variant. N Engl J Med 2021;384(20):1899–1909. doi:10.1056/NEJMoa2103055.
72. Madhi SA, Moodley D, Hanley S, et al. Immunogenicity
and safety of a SARS-CoV-2
recombinant spike protein nanoparticle vaccine
in people living with and without HIV
-1 infection: a randomised, controlled, phase 2A/2B trial. Lancet HIV
73. Sharif N, Alzahrani KJ, Ahmed SN, et al. Efficacy, immunogenicity
and safety of COVID-19 vaccines: a systematic review and meta-analysis. Front Immunol 2021;12:714170. doi:10.3389/fimmu.2021.714170.
74. Tarke A, Coelho CH, Zhang Z, et al. SARS-CoV-2
vaccination induces immunological T cell memory able to cross-recognize variants from alpha to omicron. Cell 2022;185(5):847–859 e11. doi:10.1016/j.cell.2022.01.015.
75. GeurtsvanKessel CH, Geers D, Schmitz KS, et al. Divergent SARS-CoV-2
omicron-reactive T and B cell responses in COVID-19 vaccine
recipients. Sci Immunol 2022;7(69):eabo2202. doi:10.1126/sciimmunol.abo2202.
76. Cele S, Karim F, Lustig G, et al. SARS-CoV-2
prolonged infection during advanced HIV
disease evolves extensive immune escape. Cell Host Microbe 2022;30(2):154–162.e5. doi:10.1016/j.chom.2022.01.005.
77. Corey L, Beyrer C, Cohen MS, et al. SARS-CoV-2
variants in patients with immunosuppression. N Engl J Med 2021;385(6):562–566. doi:10.1056/NEJMsb2104756.
78. Freer J, Mudaly V. HIV
and covid-19 in South Africa. BMJ 2022;376:e069807. doi:10.1136/bmj-2021-069807.
79. Gunthard HF, Wong JK, Spina CA, et al. Effect of influenza vaccination on viral replication and immune response in persons infected with human immunodeficiency virus receiving potent antiretroviral therapy. J Infect Dis 2000;181(2):522–531. doi:10.1086/315260.
80. Staprans SI, Hamilton BL, Follansbee SE, et al. Activation of virus replication after vaccination of HIV
-1-infected individuals. J Exp Med 1995;182(6):1727–1737. doi:10.1084/jem.182.6.1727.
81. Brichacek B, Swindells S, Janoff EN, et al. Increased plasma human immunodeficiency virus type 1 burden following antigenic challenge with pneumococcal vaccine
. J Infect Dis 1996;174(6):1191–1199. doi:10.1093/infdis/174.6.1191.
82. Cheeseman SH, Davaro RE, Ellison RT 3rd. Hepatitis B vaccination and plasma HIV
-1 RNA. N Engl J Med 1996;334(19):1272. doi:10.1056/NEJM199605093341916.
83. Yek C, Gianella S, Plana M, et al. Standard vaccines increase HIV
-1 transcription during antiretroviral therapy. AIDS 2016;30(15):2289–2298. doi:10.1097/QAD.0000000000001201.