9 January 2023 Episode 305: Update on HIV, COVID and vaccination

Dear colleagues,

Because I was asked to write and editorial comment for AIDS on the relation between HIV and COVID vaccination, I reviewed the literature.  Since this should be a “mature field”, I mainly restricted myself to peer-reviewed papers.  We will first explore to what extend pre-existing HIV infection influences COVID and next look at the response of PLWH on primary and booster vaccines

Par 1 Effect of HIV infection on COVID  

1. 1. AFRICA

Ep 305-1:  Nebiyat Semeredin Ahmed from Ethiopia IJID Regions Sept 2021:  PLWH with COVID-19 had a higher rate of in-hospital mortality than people without HIV, although no association was found between HIV status and the requirement for intensive care unit admission, mechanical ventilation, oxygen support, or the severity of the disease at the time of admission.  

Ep 305-2: Peter Minchella Zambia during 4 waves JAMA Network Open Dec 2022

Factors associated with in-hospital mortality included older age (> 60 vs <30 years; (aOR, 3.55; 95%CI, 2.34-5.52) and HIV infection (aOR, 1.39; 95%CI, 1.07-1.79).

Ep 305-3: Waasila Jassat South Africa  Lancet HIV Aug 2021

High risk of COVID-19 in-hospital mortality : older individuals , those with chronic comorbidities and people with HIV, particularly those not on ART)

1.2 EUROPE

Ep 305-4: Nomah Catalonia  Lancet HIV Oct 2022

Association with increased risk of severe disease were:

- Age at least 75 years (5∙2, 1∙8–15∙3),

- Non-Spanish origin (2∙1, 1∙3–3∙4),

- Various comorbidities:  neuropsychiatric (1∙69, 1∙07–2∙69), autoimmune disease (1∙92, 1∙14–3∙23), respiratory disease (1∙84, 1∙09–3∙09), and metabolic disease (2∙59, 1∙59–4∙23)

-  People living with HIV with detectable HIV viraemia and low CD4 T cell count

1. 3. NORTH AMERICA

Ep 305-5: Xueying Yang USA Lancet HIV Oct 2021

PLWH had higher odds of COVID-19 death (aOR 1∙29, 95% CI 1∙16–1∙44) and hospitalisation (1∙20, 1∙15–1∙26)

Factors:  Older age groups, male, Black, African American, Hispanic, or Latinx adults

                Lower CD4 associated with higher hospitalization and death;

Suppressed viral load with lower hospitalization

1. 4. REVIEW

Ep 305-6: Oyelade Trop Med Infect Dis Feb 2022

HIV infection is associated with more severe  COVID-19 and death in Africa, to a lesser extent in North America, while there is less of a difference between PLWH and HIV-negative controls in Europe, Asia and South-America, most probably reflecting the different degree of viral control and immune reconstitution of PLWH in these regions

1. 5. IMMUNE MECHANISMS AND VIROLOGICAL CONSEQUENCES

Ep 305-7: Nkosi eLife July 2022: Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition between WT and beta variant.

After WT infection HIV-seronegative individuals had significantly greater CD4+ T cell against the Spike protein compared to the viremic people living with HIV (PLWH), while responses in virally suppressed PLWH are similar to HIV-negative controls

In both CD4 and CD8 T cell populations, the polyfunctional cytokine responses were weaker and there was a skewing from an IFN-g dominated towards a TNF dominated response

Absolute CD4 count correlated positively with SARS-CoV-2-specific CD4+ and CD8+ T cell responses (CD4 r=0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4+ T cell responses (CD4 r=−0.7, p=0.04).

There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection.

These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern.

Ep 305-8: Cele Cell Host Microbes 2022 documented a chronic originally wild-type SARS-CoV-2 infection in a South African patient with advanced HIV disease, which evolved extensive immune escape and therefore could become a source of a new variant, partly resistant to infection or vaccine-induced antibodies.

(A) Participant characteristics over 233 days from SARS-CoV-2 diagnosis: CD4 T cell count (cells/mL), SARS-CoV-2 detection by qPCR, virus outgrowth success, and presence of anti-RBD IgG.

(B) Majority and minority SARS-CoV-2 genotypes in the swab (day 0) and outgrowth (day 6 to 190). X axis lists substitutions and deletions in spike sequence, and positions where mutations are found in variants are highlighted. AF: allele frequency.

(C) Cryogenic electron microscopy (cryo-EM) structure of the SARS-CoV-2 spike protein. The mutations in day 190 isolated virus (D190) shown as red spheres.

(D) Neutralization of day 6 isolated (D6), day 20 isolated (D20), and D190 virus by self-plasma collected days 6 to 216 and the ancestral D614G, Beta, and Delta viruses with plasma collected day 216.

Clearly, the patient acquired a number of mutations, many described in Omicron and some in gamma and lambda. The neutralization capacity of his late plasma (day 216) is weak against this heavily mutated own virus and it has also no capacity to neutralize the beta variant.

CONCLUSION Par 1

HIV infection is a risk for severe COVID and mortality, if the viral loads is not suppressed and/or if the CD4 T count is decreased.

Viremic HIV is associated with poor T cell responses to SARS-CoV-2, which may explain the tendency to disease severity.

Prolonged SARS-CoV-2 infection in a patient with advanced HIV disease led to the emergence of many variant-specific mutations, which are partly neutralization resistant

Therefore, for both individual and public health purposes, PLWH are a priority target population for vaccination

Par 2 Response to vaccination in PLWH   

2.1. Immune responses to basic vaccination

A review of 22 studies with 6522 PLWH demonstrates that after the second dose seroconversion in PLWH is slightly lower than in healthy individuals.  Messenger RNA and viral vector vaccines showed a higher seroconversion rate, while inactivated virus vaccines induced a slightly, but not significantly lower seroconversion [Ep 305-9].

The trend to diminished antibody responses detected in PLWH cohorts are in line with reports on other vaccines e.g. against Influenza [Ep 305-10]. 

Looking in more detail in European studies, seroconversion rate, anti-Spike antibodies and neutralizing titers of PLWH with CD4 T counts over 500/µL are comparable with those in healthy controls, while they are clearly reduced if CD4 T cells are below 200/µL, even these patients received a fully viral-suppressive treatment:

Ep 305-11:Hensley PLOS Medicine Oct 2022

HIV status was associated with a decreased antibody response to mRNA and Chimp Adeno vaccines

Higher antibody responses were predicted by CD4+ T cell count 250–500 cells/μL (2.845, 95% CI 1.876–4.314, p < 0.001) or >500 cells/μL (2.936, 95% CI 1.961–4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286–0.720, p = 0.001).

Cellular responses: IFN-γ, CD4+ T-cell and CD8+ T-cell responses after stimulation with SARS-CoV-2 spike peptides were comparable in PLWH and controls

Ep 305-12: Anais Corma-Gomez Clin Microbiol Infect 2022:  Severe immunosuppression is related to poorer immunogenicity to SARS-CoV-2 vaccines among people living with HIV.

Ep 305-13: Nolan Hassold AIDS 2022 Impaired antibody response to COVID-19 vaccination in advanced HIV infection

South-African PLWH under stable treatment but with incompletely suppressed viral load (under 1000 copies), responded well to full vaccination with either recombinant Spike protein (Novavax) or chimp adenovector (Astra-Zeneca) vaccines, but with lower titers [Ep 305-14 and -15].  

2.2. Level of protection after basic vaccination = vaccine effectiveness

Ep 305-16: Catherine Chambers AIDS 2022:

The Canadian COVAXHIV Study Team performed the first study on real-world effectiveness, using a test-negative approach in over 21,000 well-treated PLWH vaccinated with 2 doses of BNT162b2, mRNA-1273, or ChAdOx1 vaccines and followed up during the pre-Omicron era. 

Very similar protection against infection and severe disease amongst PLWH as observed in non-HIV subjects.

Ep 305-17:  Linda-Gail Bekker Lancet HIV 2022: single dose Ad26.COV2.S vaccine (Johnson & Johnson) showed a high effectiveness against COVID-related hospitalization and death during the beta and delta wave in South-African health care workers, including those who were HIV-positive.

2.3 Response to booster vaccination

Ep 305-18:  Andrea Antinori CID July 2022 An Italian study showing that one month after a booster dose with mRNA vaccines, PLWH with CD4 T cells > 500/µL had similar antibody and cellular responses to wild-type virus as compared to controls, but those with low CD4 T cells had reduced responses

Ep 305-19: Jongkees medRxiv 10 Aug 2022. In a Dutch cohort of PLWH with a hypo-response after a primary vaccination regimen, an additional regular dose (100 µg)  mRNA-1273 vaccination induced a robust serological response in 97% of the 84 PLWH after one month, including neutralizing antibodies to wild-type virus, as well as T-cell responses, regardless of the primary vaccination regimen or patient characteristics. 

Figure 1. Study overview. Overview of the initial COVIH study and the COVIH-BOOST substudy with the number of included participants. A total of N=66 participants with hyporesponse  after a primary vaccination regimen were enrolled in the substudy for additional mRNA-1273 vaccination and study of their immune response. N/A: not applicable

Figure 2. SARS-CoV-2 S1-specific binding antibody levels in PLWH after additional mRNA-547 1273 vaccination. Levels of S1-specific binding antibodies measured 28 days after the additional mRNA-1273 vaccination in all 66 PLWH (grey), in 22 PLWH after primary vaccination 549 with BNT162b2 (blue), in 40 PLWH after primary vaccination with ChadOx1-S (yellow), and in  four PLWH after primary vaccination with Ad26.COV2.S (red). The thick horizontal bar shows the mean S1-specific binding antibody level, also indicated above the graph, with error bars showing the standard error of the mean. LLoD is 4.81 BAU/mL, adequate responder (resp) cut-off is 300 BAU/mL (dotted line). Comparisons of timepoints were performed by paired t test. S: spike, LLoD: lower limit of detection, T0: before additional vaccination, T1: 28 days after  additional vaccination.

Figure 3. Neutralizing antibodies to SARS-CoV-2 in subgroup participants (N=40) after additional mRNA-1273 vaccination. (A) PRNT50 titer measured 28 days after the additional mRNA-1273 vaccination against the ancestral SARS-CoV-2 (D614G) and Omicron (BA.1) variant 560 after primary vaccination with ChAdOx1-S (yellow) and BNT162b2 (blue). The thick horizontal bar shows the mean neutralizing antibody titer, also indicated above the graph, with error  bars showing the standard error of the mean. LLoD is 10. Comparisons between the two different primary vaccination groups were performed using unpaired t test

Ep 305-20: Hope R. Lapointe. medRxiv Nov 2022 explored the response to a booster more extensively in Canada: they showed a similar durability of immune responses over a six months period in PLWH under suppressive treatment and healthy controls.

• In COVID naïve subjects: WT- and Omicron-specific IgG concentrations, ACE2 displacement and virus neutralization activities declined at similar rates among PLWH and healthy controls. BA.1-specific neutralization was undetectable in >80% of COVID-19 naive PLWH and >90% of controls.

• Breakthrough SARS-CoV-2 infection boosted antibody concentrations and function significantly above vaccine-induced levels in both PLWH and healthy controls, though BA.5-specific neutralization remained significantly poorer than BA.1 even after breakthrough infection, suggesting the need for a second booster in both PLWH and healthy controls. 

Ep 305-21: Bessen Front Imm Dec 2022: from Germany on the response to the second and third dose of mRNA vaccine in well treated PLWH, most with CD4 T counts slightly below the normal range:

•  Titers of neutralizing antibodies were reduced in PLWH compared to controls for WT, but even more to Delta and Omicron SARS-CoV-2 strains after the second and the third vaccination.  
• Despite the reduced CD4+ T cell count in the peripheral blood of PLWH, the CD4+ cellular response to COVID-19 vaccination was preserved.  However, this response was weak overall.
• During the follow-up 8 out of 71 PLWH acquired a breakthrough infection after the second dose and 6 additional ones after the third dose, but no details on severity are provided.

Percentage of activated (CD137+ CD154+) CD4 T cells after Spike (S) peptide stimulation is low overall, it doesn’t increase with primary vaccination or booster and is not different between controls and PLWH

Ep 305-22: In contrast to Bessen, El Moussaoui in J Infect dec 2022 find after the third dose that:

• Increase in humoral immune responses was similar between PLWH and HIV-negative individuals.
• Although SARSCoV-2 specific IFN- ɣ production increased after the third dose, it remained significantly lower among SARS-CoV-2 naive PLWH compared to HCWs.
• Hybrid immunity induces similar T-cell responses between people living with HIV and HIV-negative individuals.

Fig. 1A. Comparison of cellular and humoral immune responses between people living with HIV and HIV-negative healthcare workers before administration of the third dose of SARS-CoV-2 mRNA vaccine (T0).

SARS-CoV-2-specific IFN- γ release for Ag1 (A 1 ), SARS-CoV-2-specific IFN- γ release for Ag2 (A 2 ), Anti-S IgG (A 3 ), neutralising antibody titres against Wild-type variant (A 4 ), and neutralising antibody titres against Omicron variant (A 5 ) were measured and compared between PLWH (n = 119) and HCWs (n = 79) who had received two doses of the SARS-CoV-2 vaccine.

Dots represent subjects, whiskers represent median and IQR, and horizontal dashed line corresponds to the positivity cutoff (IFN- γ > 0.15 IU/mL and

anti-S IgG ≥ 33.8 BAU/mL were considered positive). Statistics were calculated using adjusted linear regression models on log10-transformed variables. Exact number of participants in each group is indicated in Table S1.

Fig 1B. Evolution of cellular and humoral immune responses following the third dose of SARS-CoV-2 mRNA vaccine in SARS-CoV-2 naive and experienced PLWH.

SARS-CoV-2-specific IFN- γ release for Ag1 (B 1 ), SARS-CoV-2-specific IFN- γ release for Ag2 (B 2 ), Anti-S IgG (B 3 ), neutralising antibody titres against Wild-type variant (B 4 ), and neutralising antibody titres against Omicron variant (B 5 ) were measured and compared before (T0) and after a third dose (T1) of the SARS-CoV-2 mRNA vaccine among PLWH (n = 80), divided into 3 subgroups according to history of SARS-CoV-2 infection (naive, experienced before T0, and experienced between T0 and T1).

Dots represent subjects, whiskers represent median and IQR, and horizontal dashed line corresponds to the positivity cutoff (IFN- γ > 0.15 IU/mL and anti-S IgG ≥ 33.8 BAU/mL were considered positive). Statistics were calculated using linear regression models on log10-transformed variables. Exact number of participants for each group is indicated in Table S5.

Fig 1C. Comparison of cellular and humoral immune responses between people living with HIV and healthcare workers after administration of the third dose of SARS-CoV-2 mRNA vaccine (T1). SARS-CoV-2-specific IFN- γ release for Ag1 (C 1 ), SARS-CoV-2-specific IFN- γ release for Ag2 (C 2 ), Anti-S IgG (C 3 ), neutralising antibody titres against Wild-type variant (C 4 ), and neutralising antibody titres against Omicron variant (C 5 ) were measured and compared between SARS-CoV-2 experienced and naive PLWH (n = 80) and HCWs (n = 51) two to eight weeks after administration of a third dose of the SARS-CoV-2 mRNA vaccine. Dots represent subjects, whiskers represent median and IQR, and horizontal dashed line corresponds to the positivity cutoff (IFN- γ > 0.15 IU/mL and anti-S IgG ≥ 33.8 BAU/mL were considered positive). Statistics were calculated using adjusted linear regression models on log10-transformed variables. Exact number of participants for each group is indicated in Table S6.

CONCLUSION

In PLWH under viral suppressive treatment and with high CD4 T cell counts basic and booster vaccination induce presumably protective humoral and cellular immune responses, very similar to HIV-negative controls.  

A booster with the most potent vaccine (mRNA 1273) can rescue hypo-responsiveness in PLWH, but nevertheless immune responses wane with time and are weak against omicron subvariants, just like in HIV (-) control subjects.

The effectiveness of vaccination in well-treated PLWH is satisfactory.  Nevertheless breakthrough infections (BTI) occur: it is not clear from published data whether BTI are  more severe in PLWH in general, but they do provide hybrid immunity, just like in HIV(-) controls.

As expected, immune responses are weaker in PLWH with low CD4 T cell counts, but it is unclear whether these subjects suffer from more frequent or more severe BTI.

On one hand uncontrolled HIV infection could result in chronic SARS-CoV-2 infection with the risk of developing new immune-evasive mutants that could cause new epidemic waves in the general population and, on the other hand, ageing PLWH, even those who are well-treated and immunocompetent, are known to suffer from more comorbidities than their seronegative peers.

Therefore it is important both for individual and public health that PLWH are encouraged to receive booster vaccination against new variants, as soon as they become available.