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. 2022 Oct 27;19(10):e1003979. doi: 10.1371/journal.pmed.1003979

Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: A nationwide prospective cohort study

Kathryn S Hensley 1, Marlou J Jongkees 1,#, Daryl Geers 2,#, Corine H GeurtsvanKessel 2, Yvonne M Mueller 3, Virgil A S H Dalm 3,4, Grigorios Papageorgiou 5, Hanka Steggink 6, Alicja Gorska 1, Susanne Bogers 2, Jan G den Hollander 7, Wouter F W Bierman 8, Luc B S Gelinck 9, Emile F Schippers 10,11, Heidi S M Ammerlaan 12, Marc van der Valk 13,14, Marit G A van Vonderen 15, Corine E Delsing 16, Elisabeth H Gisolf 17, Anke H W Bruns 18, Fanny N Lauw 19, Marvin A H Berrevoets 20, Kim C E Sigaloff 21, Robert Soetekouw 22, Judith Branger 23, Quirijn de Mast 24, Adriana J J Lammers 25, Selwyn H Lowe 26, Rory D de Vries 2, Peter D Katsikis 3, Bart J A Rijnders 1, Kees Brinkman 6, Anna H E Roukens 11,‡, Casper Rokx 1,‡,*
Editor: James G Beeson27
PMCID: PMC9612532  PMID: 36301821

Abstract

Background

Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH.

Methods and findings

We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44–60] years, 85.5% male) and 440 controls (median age 43 [IQR 33–53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/μL (IQR 520–913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322–1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508–0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based 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). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients.

Conclusions

After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required.

Trial registration

The trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214.

Kathryn Sietske Hensley and colleagues investigate the immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands.

Author summary

Why was this study done?

  • The efficacy of SARS-CoV-2 vaccines in people living with HIV (PLWH) is not well characterised.

  • HIV has been repeatedly associated with lower immune responses to other vaccines, and this diminished response is strongly correlated with CD4+ T-cell count.

  • The SARS-CoV-2 vaccines BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S showed good protection against severe COVID-19 and hospitalisation in phase III registration trials; however, the number of PLWH in these trials was very limited.

What did the researchers do and find?

  • We initiated a nationwide prospective study including 1,154 PLWH and 440 HIV-negative controls.

  • We show that lower antibody levels are seen in PLWH compared to controls after completion of the vaccination schedule, regardless of the vaccine received.

  • All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In multivariable analyses, having HIV had the largest negative effect on antibody responses following vaccination, more than both age and sex.

  • Following mRNA vaccination, the antibody response was higher in PLWH with CD4+ T-cell counts between 250 and 500 cells/μL or higher than 500 cells/μL (both p < 0.001), while those with <250 cells/μL had a lower response. In PLWH, age above 65 years and being born as male were associated with lower antibody concentrations as well (both p < 0.001).

What do these findings mean?

  • Clinicians should particularly be aware of potential lower vaccine responses in elderly PLWH and those with lower cellular immunity or evidence of acquired immunodeficiency syndrome.

  • PLWH may require additional vaccinations on top of standard regimens to achieve and keep protection against SARS-CoV-2 at similar levels to HIV-negative controls.

  • In these participants, with the vaccines studied, mRNA-based vaccine strategies are to be preferred over vector-based ones.

Introduction

At the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, and the ensuing and ongoing pandemic led to the loss of millions of lives. Highly effective vaccines were quickly developed, and mass vaccination campaigns have become the cornerstone to prevent fatal coronavirus disease (COVID-19) and to quell this pandemic. Four vaccines are currently approved for use in the Netherlands [1–5].

HIV infection is associated with worse COVID-19 outcomes although the underlying mechanism is not yet clear [6]. In most countries, people living with HIV (PLWH) were therefore prioritised for SARS-CoV-2 vaccination. PLWH show diminished responses to a wide variety of vaccines such as hepatitis B and seasonal influenza vaccines compared to HIV-negative individuals [7,8]. This might also hold true for SARS-CoV-2 vaccines. Indicative of potentially lower responses to SARS-CoV-2 vaccines could be that after SARS-CoV-2 infection, lower IgG concentrations and neutralising antibody titres were found in PLWH compared to controls [9]. Data are scarce on SARS-CoV-2 vaccination responses in PLWH; some PLWH were included in the large phase III trials, but data for these participants were not published with the results of these trials [1–5]. Small studies using the ChAdOx1-S vaccine in the UK and South Africa in relatively young PLWH with high CD4+ T-cell counts showed PLWH having comparable responses to controls [10,11]. As for BNT162b2, similar results were shown in a limited number of PLWH [12–14]. The identification of risk factors for a reduced response to SARS-CoV-2 vaccines in PLWH is important as it will help to improve vaccination strategies in PLWH. A good understanding of vaccination response in PLWH is even more important now that variants of concern (VOCs) continue to arise and partially escape vaccine-induced immunity [15], especially considering the possibility of VOCs arising in PLWH unable to clear the virus due to an untreated HIV infection [16].

We hypothesised that SARS-CoV-2 vaccine response in PLWH would be lower than in HIV-negative controls. Our main aim was therefore to investigate the immunogenicity of SARS-CoV-2 vaccinations in PLWH with the vaccines currently approved in the Netherlands—BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S—compared to HIV-negative controls. Additionally, we reviewed the reactogenicity of the vaccines in PLWH.

Methods

Study design and participants

We performed a prospective observational cohort study in 22 of the 24 HIV treatment centres in the Netherlands. Participants were recruited via treating physicians or nurses specialised in HIV care. Individuals who were 18 years or older and had a confirmed HIV infection were eligible and were invited for SARS-CoV-2 vaccination by Dutch public health services. Participants with a history of previous SARS-CoV-2 infection demonstrated by PCR or detectable SARS-CoV-2 anti-spike antibodies in serum before vaccination were excluded. Inclusion was stratified according to vaccine type (mRNA or vector), sex assigned at birth, age (18–55, 56–65, or >65 years), and most recent CD4+ T-cell count (<350 and ≥350 cells/μL). In order to recruit a study population that best represented the Dutch population of PLWH, we continuously monitored recruitment across these strata, and strata were closed for enrolment when a sufficient number had been recruited [17].

Participants received BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S according to manufacturer’s regulations as part of the Dutch SARS-CoV-2 vaccination campaign (S1 Text). Vaccination response data from HIV-negative controls were obtained from 2 separate concurrent studies. The first cohort consisted of healthcare workers from the Erasmus University Medical Centre in Rotterdam who were enrolled in a prospective cohort study (n = 385) [18]. Healthcare workers received BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S according to national regulations as described above. The second group consisted of participants who served as non-immunocompromised controls in the Vaccination Against Covid in Primary Immune Deficiencies (VACOPID) study investigating the mRNA-1273 vaccine in people with inborne errors of immunity (n = 55) [19]. They received 2 mRNA-1273 vaccines 4 weeks apart with blood sampling 4 weeks after the second vaccination. None of the controls had a history of COVID-19.

This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist).

Clinical procedures

Between 14 February and 7 September 2021, 1,269 participants were included. Blood samples for serology were collected up to 6 weeks before vaccination in 1,269 participants (pre-vaccination). During study follow-up, 53 participants were excluded after a positive anti-spike antibody test at baseline sampling, and 51 participants were lost to follow-up. Four to six weeks after the completed vaccination schedule, blood draws were performed in 1,165 participants (post-vaccination). In a subgroup of participants willing to participate in extra sampling, additional blood samples were collected for peripheral blood mononuclear cells (PBMCs) at any of the study visits (pre-vaccination, n = 23; post-vaccination, n = 45) or for serology 21 days (±3 days) after the first vaccination (inter-vaccination) (n = 43). Participants were scheduled for longitudinal blood sampling for 2 years for additional analyses, which will be reported separately.

Study variables were collected in an electronic case record file. Study variables that were collected included year of birth, sex assigned at birth (male/female), current use of combination antiretroviral therapy (cART) (yes/no), most recent plasma HIV RNA (copies/mL), most recent CD4+ T-cell count (cells/μL), and nadir CD4+ T-cell count (cells/μL).

Participants received a paper diary or a link to an online questionnaire to record adverse events (AEs) from a predefined list and medication use occurring in the 7 days following each vaccination.

Laboratory procedures

All serum samples were collected via venepuncture at participating centres. Serum samples before vaccination were analysed at the laboratory of the individual treating centres with the available SARS-CoV-2 antibody test: Wantai SARS-CoV-2 total IgG and IgM ELISAs (Beijing Wantai Biological Pharmacy Enterprise, China), Abbott ARCHITECT SARS-CoV-2 IgG (Abbott Laboratories, Abbott Park, Illinois, US), Siemens Atellica IM SARS-CoV-2 IgG (sCOVG) serology assay (Siemens Healthineers Nederland, The Hague, the Netherlands), or LIAISON by DiaSorin (Saluggia, Italy), depending on local availability and according to the manufacturer’s instructions. Serum samples post-vaccination were transported for testing at the Department of Viroscience, Erasmus University Medical Centre, the Netherlands. Binding antibodies against the SARS-CoV-2 spike (S1) were quantified with a validated IgG trimeric chemiluminescence immunoassay (LIAISON, DiaSorin) with a lower limit of detection at 4.81 binding antibody units (BAU)/mL and a cutoff level for positivity at 33.8 BAU/mL [20].

PBMCs were isolated by density gradient centrifugation (Ficoll-Hypaque, GE Healthcare Life Sciences) and collected in RPMI-1640 (Life Technologies) supplemented with 3% foetal bovine serum (FBS). PBMCs were washed 3 times, frozen in freezing medium (90% FBS, 10% dimethyl sulfoxide [DMSO]), and stored in liquid nitrogen until use.

We used enzyme-linked immune absorbent spot (ELISpot) assays to quantify interferon-γ (INF-γ) secretion in response to SARS-CoV-2 peptides. ELISpot assays were performed on cryopreserved PBMCs using a commercial kit (ImmunoSpot, Cellular Technology). PBMCs were stimulated with peptide pools consisting of SARS-CoV-2 spike protein, SARS-CoV-2 nucleocapsid protein (to exclude PLWH recently infected with SARS-CoV-2), myelin oligodendrocyte glycoprotein (MOG) as a negative control, and CEFX (peptide epitopes from different infectious agents) as a positive control (S2 Text). Results are expressed as spot-forming cells (SFCs) per million PBMCs. To exclude nonspecific stimulation of T cells by peptides, specific S responses were calculated by subtracting mean MOG responses from mean spike responses.

T-cell responses were further characterised by activation-induced marker (AIM) assay. PBMCs were incubated with SARS-CoV-2 peptide pools covering the entire spike protein of the WuhanHu1 (wild-type) or B.1.617.2 (Delta) variant. Following stimulation, cells were stained and measured by flow cytometry (FACSLyric, BD Biosciences; S3 Text). SARS-CoV-2-reactive T cells were identified as CD137+OX40+ for CD4+ subtype or CD137+CD69+ for CD8+ subtype. On average, 300,000 cells were measured. The gating strategy can be found in S1 Fig.

Outcomes

The primary outcome was the magnitude of the anti-spike SARS-CoV-2 IgG response in PLWH 4–6 weeks after the completed vaccination schedule with BNT162b2 or mRNA-1273. This endpoint was chosen because primarily mRNA vaccines were allocated to PLWH in the Netherlands. Secondary outcomes included the antibody response in PLWH after the completed vaccination schedule with ChAdOx1-S or Ad26.COV2.S, and variables associated with the magnitude of antibody level (vaccine type [BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S], sex assigned at birth [male or female], age [birth year 1965–2002, 1955–1964, or 1954 or earlier], nadir CD4+ T-cell count [<250, 250–500, or >500 cells/μL], and most recent CD4+ T-cell count [<250, 250–500, or >500 cells/μL]). Variables associated with hyporesponse and the presence of an antibody response were also analysed (vaccine group [mRNA or vector], sex at birth [male or female], age group [birth year 1965–2002, 1955–1964, or 1954 or earlier], nadir CD4+ T-cell count [<250, 250–500, or >500 cells/μL], and most recent CD4+ T-cell count [<250, 250–500, or >500 cells/μL]). We defined a hyporesponse as lower than 300 BAU/mL, based on previous studies that showed a correlation of antibody concentration of 300 BAU/mL with a neutralising capacity of 1:40 in the wild-type variant [21,22]. The cutoff level for positivity in the DiaSorin assay was 33.8 BAU/mL [20]. In subgroup analyses, anti-spike SARS-CoV-2-specific T-cell response and antibody response 21 days after the first vaccine dose were evaluated. Lastly, we evaluated the tolerability of the administered vaccines by monitoring local and systemic vaccine-related AEs. Severity of reactogenicity was measured as mild (symptoms present but no functional impairment or medication needed), moderate (necessitating medication, no functional impairment), or severe (impairing daily functioning). Serious AEs (SAEs) were assessed for likeliness of association with vaccination by the participating site principal investigator and physician.

Sample size and statistical analysis plan

When the study started, we did not have confirmed availability of a control group due to the rapid initiation of the national immunisation campaign. We justified the sample size by calculating that 556 PLWH receiving mRNA vaccines would be sufficient to detect, with >80% power, a serological response rate of 90% or lower compared to a hypothetical 95% response rate in controls. When the control group was confirmed, and before the data lock and endpoint analyses, we amended the protocol to update the sample size calculation. Accounting for the imbalance in the number of controls versus PLWH with BNT162b2 and mRNA-1273 vaccinations, we found that 286 controls were sufficient to detect a 20% lower antibody response in PLWH with >80% power and alpha 5%.

Descriptive data are presented as median (interquartile range [IQR]) or n (%). A multivariable linear regression model was used for the analysis of the anti-spike SARS-CoV-2 IgG response. The outcome was transformed using the natural logarithm plus 1 unit: ln(anti-spike SARS-CoV-2 IgG + 1) in order to meet the model assumptions. All participants whose sample was received in the central laboratory for testing who completed the vaccination scheme were included in the analysis (per protocol). The difference between PLWH and controls was captured by the corresponding regression coefficient and 95% confidence interval (CI). The model was further adjusted for differences in vaccine type, age, and sex. A multivariable linear regression model was also used to quantify the difference in ln(anti-spike SARS-CoV-2 IgG + 1) between PLWH and controls for the subset in the sample vaccinated with vector vaccines. A similar model was used to quantify the effect of age, sex, vaccine type, most recent CD4+ T-cell count, and antibody concentration in PLWH. In addition, multivariable logistic regression models were used to calculate odds ratios (ORs) with 95% CIs for the effects of sex, age, nadir CD4+ T-cell count, most recent CD4+ T-cell count, HIV RNA viral load, and vaccine group in PLWH on having a hyporesponse or the presence of a response. In subgroup participants, we evaluated differences from baseline to inter-vaccination and from inter- to post-vaccination, as well as AIM data comparing pre- and post-vaccination time points, by Wilcoxon matched-pairs signed rank test. ELISpot pre- to post-vaccination data and AIM data comparing PLWH and controls were analysed by Mann–Whitney U tests.

Data were analysed using IBM SPSS Statistics 25, R (v. 4.1.2), and GraphPad Prism 8. Flow cytometry data were analysed using FlowJo software version 10.8.1.

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Ethical considerations

The trial was performed in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and the Dutch Medical Research Involving Human Subjects Act (WMO). Written informed consent was obtained from all participants. The trial was reviewed and approved by the Medical Research Ethics Committees United Nieuwegein (MEC-U, reference 20.125). The trial was registered in the Netherlands Trial Register (NL9214).

Results

Baseline characteristics

Between 14 February and 7 September 2021, 1,269 PLWH were enrolled (Fig 1). At sampling before vaccination, 53 (4.2%) PLWH had antibodies against SARS-CoV-2 spike protein above the test cutoff and were excluded. Overall, 30 PLWH were lost to follow-up (2.4%), 5 decided against vaccination after inclusion (0.4%), 8 withdrew from the study (0.6%), and 10 samples were not stored adequately or not received in the central laboratory for testing (0.8%). One participant was excluded from the final analysis because they received 2 different vaccines (ChAdOx1-S and BNT162b2). In the final analysis, 76.6% of PLWH received BNT162b2, 8.7% received mRNA-1273, 13.0% received ChAdOx1-S, and 1.7% received Ad26.COV2.S. Included PLWH had a median age of 53 years (IQR 44–60), 85.5% were men, and they had a median CD4+ T-cell count before vaccination of 710 cells/μL (IQR 520–913) (Table 1). The vast majority (99.0%) were on cART and had a suppressed plasma HIV RNA level (97.7% had <50 copies/mL). The control group consisted of 440 people, of whom 94 were vaccinated with BNT162b2 (21.4%), 247 with mRNA-1273 (56.1%), 26 with ChAdOx1-S (5.9%), and 73 with Ad26.COV2.S (16.6%). Their median age was 43 (IQR 33–53), and 28.6% were men. The age distribution across vaccine groups differed, with the majority of PLWH receiving ChAdOx1-S being 56–65 years of age compared to 15%–25% for the other vaccines (S1 Table). Age differences were also seen between the PLWH and control groups, with fewer participants of older ages in the control group. Between the control group and PLWH, there was also a difference in inclusion by sex. All other factors were similar across groups. In the subgroups of PLWH, baseline characteristics reflected the characteristics of included PLWH, with most participants receiving the BNT162b2 vaccine (66.0%–95.3%) and being male (76.6%–85.7%) (S2 Table).

Fig 1. Flow chart of included PLWH.

Fig 1

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*Participants who tested positive for SARS-CoV-2 antibodies in serum at baseline measurement were excluded from further articipation †Samples were not stored adequately or were not sent to be analysed in the central laboratory at the Erasmus University Medical Centre. ††One participant received a combination of ChAdOx1-S and BNT162b2 vaccines and was therefore not included in the per protocol analysis. PLWH, people living with HIV.

Table 1. Baseline characteristics of HIV-negative controls and PLWH.

Characteristic HIV-negative participants People living with HIV
Overall
N = 440		 mRNA vaccines1
N = 341 (77.5%)		 Vector vaccines2
N = 99 (22.5%)		 Overall
N = 1,154		 mRNA vaccines1
N = 984 (85.3%)		 Vector vaccines2
N = 170 (14.7%)
Sex assigned at birth
 Male 126 (28.6%) 104 (30.5%) 22 (22.2%) 987 (85.5%) 839 (85.2%) 148 (87.1%)
 Female 314 (71.4%) 237 (69.5%) 77 (77.8%) 167 (14.5%) 145 (14.8%) 22 (12.9%)
Age category
 18–55 years 352 (80.0%) 284 (83.3%) 68 (68.7%) 703 (60.9%) 674 (68.5%) 29 (17.1%)
 56–65 years 74 (16.8) 43 (12.6%) 31 (31.3%) 291 (25.2%) 157 (16.0%) 134 (79.3%)
 >65 years 14 (3.2%) 14 (4.1%) 0 160 (13.9%) 153 (15.6%) 7 (4.1%)
On cART
 Yes NA NA NA 1,142 (99.0%) 972 (98.8%) 170 (100%)
 No NA NA NA 12 (1.0%) 12 (1.2%) 0
Most recent plasma HIV viral load
 <50 copies/mL NA NA NA 1,127 (97.7%) 960 (97.6%) 167 (98.2%)
 ≥50 copies/mL NA NA NA 27 (2.3%) 24 (2.4%) 3 (1.8%)
Most recent CD4+ T-cell count
 <250 cells/μL NA NA NA 41 (3.6%) 35 (3.6%) 6 (3.5%)
 250–500 cells/μL NA NA NA 224 (19.4%) 189 (19.2%) 35 (20.6%)
 >500 cells/μL NA NA NA 889 (77.0%) 760 (77.2%) 129 (75.9%)
Nadir CD4+ T-cell count
 <250 cells/μL NA NA NA 443 (38.4%) 365 (37.1%) 78 (45.9%)
 250–500 cells/μL NA NA NA 376 (32.6%) 330 (33.5%) 46 (27.1%)
 >500 cells/μL NA NA NA 152 (13.2%) 133 (13.5%) 19 (11.2%)
 Unknown NA NA NA 183 (15.9%) 156 (15.9%) 27 (15.9%)
Days between doses * 28 (25–28) 28 (25–28) 56 (56–70) 35 (35–36) 35 (35–36) 70 (49–77)
Days between second† vaccination and blood draw 29 (27–33) 28 (25–31) 30 (28–32) 30 (28–34) 30 (28–34) 30 (28–34)
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Data are n (%) or median (IQR).

1BNT162b2 or mRNA-1273.

2ChAdOx1-S or Ad26.COV2.S.

*Does not apply for Ad26.COV2.S.

†First and only vaccination for Ad26.COV2.S.

cART, combination antiretroviral therapy; IQR, interquartile range; NA, not applicable.

Humoral responses

In all vaccines investigated, after completion of the vaccination schedule, antibody concentrations were lower in PLWH compared to controls (Fig 2). In participants vaccinated with an mRNA vaccine, the geometric mean concentration (GMC) was 1,418 BAU/mL in PLWH (95% CI 1,322–1,523) and 3,560 BAU/mL in controls (95% CI 3,301–3,840). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. Nine PLWH had a response below the limit of detection. With regard to the primary endpoint, after adjusting for age, vaccine, and sex, HIV infection remained associated with a 39.35% lower antibody concentration in PLWH compared to HIV-negative controls receiving an mRNA vaccine (0.607, 95% CI 0.508–0.725, p < 0.001) (S3 Table). The estimated effect of having an HIV infection was larger than the estimated effects of male sex (23.05% [0.769, 95% CI 0.667–0.888]) and age over 65 years (35.47% [0.645, 95% CI 0.544–0.765]), which were both significantly associated with a worse vaccine response (p < 0.001 for both).

Fig 2. Antibody concentration in PLWH and controls after vaccination.

Fig 2

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Anti-spike SARS-CoV-2 binding antibodies after BNT162b2 (HIV-negative, n = 94; PLWH, n = 884), mRNA-1273 (HIV-negative, n = 247; PLWH, n = 100), ChAdOx1-S (HIV-negative, n = 26; PLWH, n = 150), or Ad26.COV2.S (HIV-negative, n = 73; PLWH, n = 20) vaccination in PLWH and the HIV-negative control group. The thick horizontal bar shows the geometric mean concentration, also indicated in the numbers above the graphs, with error bars showing geometric standard deviation. The dotted lines show the lower limit of detection of the performed test (4.81 BAU/mL), the positivity cutoff (33.8 BAU/mL), and the hyporesponse cutoff (300 BAU/mL). BAU, binding antibody units; LLoD, lower limit of detection; PLWH, people living with HIV; S, spike.

Regarding factors possibly related to antibody responses in PLWH who received mRNA vaccines, receiving mRNA-1273 was associated with a 57.15% higher response than receiving BNT162b2 (1.572, 95% CI 1.225–2.018, p < 0.001) (S4 Table). Male sex (0.693, 95% CI 0.555–0.865, p = 0.001) and age over 65 years (0.654, 95% CI 0.526–0.814, p < 0.001) were associated with lower responses of 30.72%, and 34.56%, respectively. We found no association between nadir CD4+ T-cell count and antibody responses, but found a significant effect of 54.62% lower antibodies when the HIV RNA level was over 50 copies/mL (0.454, 95% CI 0.286–0.720, p = 0.001). The largest effect on antibody levels was associated with having a current CD4+ T-cell count between 250 and 500 cells/μL (2.845, 95% CI 1.876–4.314) or over 500 cells/μL (2.936, 95% CI 1.961–4.394) (both p < 0.001), with increased antibody concentrations of 184.34% and 193.59%, respectively, compared to PLWH with CD4+ T-cell count under 250 cells/μL.

In participants receiving vector vaccines, after adjustment, HIV was significantly associated with a 39.47% lower antibody response, comparable to that for mRNA vaccines (0.605, 95% CI 0.387–0.945, p = 0.027) (S5 Table). Within this group of PLWH receiving vector vaccines, unlike mRNA vaccines, age, sex, and a detectable viral load were not associated with antibody responses, but receiving Ad26.COV2.S was associated with a 87.67% lower response (0.123, 95% CI 0.051–0.300, p < 0.001) and having a recent CD4+ T-cell count of 250 to 500 cells/μL or over 500 cells/μL was associated with a better response (both p < 0.001) (S6 Table).

Hyporesponse percentages, as well as the percentages of participants with no response, were higher for every vaccine in PLWH compared to controls (S1 Table). In PLWH, after adjustment, receiving a vector vaccine (p < 0.001, OR 0.036), age over 65 years (p < 0.001, OR 0.282), and viral load over 50 copies/mL (p = 0.017, OR 0.266) were associated with an antibody response under 300 BAU/mL (S7 Table). Having a most recent CD4+ T-cell count between 250 and 500 cells/μL or over 500 cells/μL was significantly associated with an antibody response of 300 BAU/mL or higher (both p < 0.001, OR 8.143 and 9.177, respectively). Sex and nadir CD4+ T-cell count were not associated with hyporesponse. When looking at the presence of a response in PLWH, receiving a vector vaccine (p < 0.001, OR 0.029) was associated with having no antibody response (<33.8 BAU/mL) (S8 Table). Being 56 to 65 years of age (p = 0.009, OR 3.697) and having most recent CD4+ T-cell count between 250 and 500 cells/μL or over 500 cells/μL (both p < 0.001, OR 7.573 and 16.894, respectively) were significantly associated with an antibody response of ≥33.8 BAU/mL. Sex, viral load, and nadir CD4+ T-cell count were not associated with having no antibody response.

In the subgroup of PLWH in whom extra sampling was performed 21 days after the first vaccination (n = 43, 95.3% with BNT162b2), we found a response rate of 83.3%, with a GMC of 148 BAU/mL in between vaccinations and 1,952 BAU/mL after vaccinations (S2 Fig).

Cellular responses

In the ELISpot assay, spike-specific T-cell responses measured as IFN-γ after deduction of MOG, increased from a median of 27.5 SFCs per million PBMCs before vaccination to 152.5 SFCs per million PBMCs post-vaccination (p = 0.002) (Fig 3A). mRNA and vector vaccine responses are shown separately in S3A and S3B Fig, and the responses after subtraction of DMSO with medium control are shown in S3C Fig. In PLWH, stimulating PBMCs with the negative control peptide pool MOG already induced a IFN-γ response, resulting in high background (S4 Fig). In order to determine whether any participants had SARS-CoV-2 infections that were missed via anti-spike SARS-CoV-2 antibody testing, nucleocapsid was added to the assay. No responses for nucleocapsid were seen after subtraction of MOG. Additionally, CD4+ and CD8+ T-cell responses were assessed in an AIM assay. SARS-CoV-2-specific CD4+ T-cell (CD137+OX40+) and CD8+ T-cell responses (CD137+CD69+) both increased compared to baseline following vaccination and after correction for DMSO (p = 0.005 and p = 0.008, respectively) (Fig 3B and 3C, respectively). CD4+ and CD8+ T-cell responses in PLWH against the Delta variant were similar before and after vaccination. Importantly, both CD4+ and CD8+ T-cell responses were of similar magnitude between PLWH and HIV-negative individuals.

Fig 3. Cellular immune responses against SARS-CoV-2 in subgroup participants (PLWH).

Fig 3

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(A) Cellular immune response to wild-type spike by ELISpot assay (Pre, n = 23; Post, n = 45): IFN-γ SFCs after subtraction of MOG. Statistics performed using Mann–Whitney U test: p = 0.002. Negative responses: Pre, 8; Post, 5. (B) Cellular immune response to wild-type and Delta spike in AIM assay (n = 14): percentage of CD4+ CD137+ OX40+ T-cells after subtraction of DMSO. Dotted line shows the LLoD at 0.001%. Statistics between pre- and post-vaccination for WT in PLWH performed using Wilcoxon matched-pairs signed rank test (p = 0.005); pre- and post-vaccination for Delta: ns. Statistics between PLWH and controls with Mann–Whitney U test: not significant. (C) Cellular immune response to wild-type and Delta spike in AIM assay (n = 14): percentage of CD8+ CD137+ CD69+ T-cells after subtraction of DMSO. Dotted line shows the LLoD at 0.001%. Statistics performed using Wilcoxon matched-pairs signed rank test (p = 0.008); pre- and post-vaccination for Delta: ns. Statistics between PLWH and controls with Mann–Whitney U test: not significant. Green circles: mRNA vaccines; blue squares: vector-based vaccines. Pre: before vaccination; Post: 4–6 weeks after second vaccination. AIM, activation-induced marker; BAU, binding antibody units; cART, combination antiretroviral therapy; DMSO, dimethyl sulfoxide; ELISpot, enzyme-linked immune absorbent spot; GMC, geometric mean concentration; INF-γ, interferon-γ; LLoD, lower limit of detection; MOG, myelin oligodendrocyte glycoprotein; PBMC, peripheral blood mononuclear cell; PLWH, people living with HIV; SFC, spot-forming cell; WT, wild type.

Reactogenicity

In PLWH, the questionnaire to record AEs and medication use was completed 1,039 (90.0%) times after the first vaccination and 1,026 (90.4%) times after the second vaccination. Overall, more than half (52.4%) of the participants reported any AE (Table 2). For those who received 2 doses, the frequency of AEs did not increase after the second vaccination (first dose, 55.2%; second dose, 49.6%). The percentage of participants reporting AEs after the first and second vaccination, respectively, was 55.2% and 48.0% for BNT162b2, 62.2% and 70.1% for mRNA-1273, and 51.8% and 46.0% for ChAdOx1-S, and after the single Ad26.COV2.S vaccination was 47.4%. The most reported local reaction was pain at the injection site (44.4%). The most common systemic reactions were myalgia (13.0%) and headache (18.3%). When AEs occurred, most were mild (1,159, 65.2%) or moderate (523, 29.4%) in severity and self-limiting (Fig 4). Analgesic or antipyretic drug use was necessary in 346 (16.8%) of all participants, for a cumulative 769 AEs, of which 400 (52.0%) were moderate and 57 (7.4%) were severe AEs. Paracetamol (81.2%) was most commonly used. Ten SAEs were reported, and all were considered unrelated to vaccination. One participant visited the emergency department 3 days after vaccination with pain in the arm and chest and shortness of breath, in whom a pulmonary embolism was excluded and symptoms resolved. Two participants were admitted for a chronic obstructive pulmonary disease exacerbation. The 7 other SAEs were elective heart surgery, intestinal perforation after infection, Campylobacter jejuni infection, bicycle accident, pyloric stenosis, hip fracture after a fall, and death due to a cardiac arrest. There was no discontinuation of the vaccination series due to vaccine-related AEs.

Table 2. Reactogenicity in PLWH.

Adverse event Overall
N = 2,065		 BNT162b2
N = 1,593 (77.1%)		 mRNA-1273
N = 177 (8.6%)		 ChAdOx1-S
N = 276 (13.4%)		 Ad26.COV2.S
N = 19 (0.9%)
1st dose
n = 791 (49.7%)		 2nd dose
n = 802 (50.3%)		 1st dose
n = 90 (50.8%)		 2nd dose
n = 87 (49.2%)		 1st dose
n = 139 (50.4%)		 2nd dose
n = 137 (49.6%)
Any AE 1,083 (52.4%) 437 (55.2%) 358 (48.0%) 56 (62.2%) 61 (70.1%) 72 (51.8%) 63 (46.0%) 9 (47.4%)
Local AE
 Pain at the injection site 917 (44.4%) 393 (49.7%) 325 (40.5%) 52 (57.8%) 57 (65.5%) 51 (36.7%) 32 (23.4%) 7 (36.8%)
 Redness at the injection site 83 (4.0%) 27 (3.4%) 29 (3.6%) 5 (5.6%) 7 (8.0%) 7 (5.0%) 8 (5.8%) 0
Systemic AE
 Generalised myalgia 269 (13.0%) 84 (10.6%) 107 (13.3%) 15 (16.7%) 26 (29.9%) 21 (15.1%) 13 (9.5%) 3 (15.8%)
 Fever 72 (3.5%) 14 (1.8%) 26 (3.2%) 4 (4.4%) 15 (17.2%) 8 (5.8%) 5 (3.6%) 0
 Headache 377 (18.3%) 126 (15.9%) 134 (16.7%) 20 (22.2%) 28 (32.2%) 41 (29.5%) 24 (17.5%) 4 (21.1%)
 Rash other than injection site 19 (0.9%) 12 (1.5%) 2 (0.2%) 1 (1.1%) 3 (3.4%) 0 0 1 (5.3%)
 Lymphadenopathy 41 (2.0%) 13 (1.6%) 18 (2.2%) 2 (2.2%) 5 (5.7%) 0 3 (2.2%) 0
Medication use
 Any medication 346 (16.8%) 116 (14.7%) 120 (15.0%) 19 (21.1%) 26 (29.9%) 34 (24.5%) 23 (16.8%) 2 (10.5%)
 Paracetamol 281 (81.2%) 95 (81.9%) 97 (80.8%) 16 (84.2%) 22 (84.6%) 30 (88.2%) 21 (91.3%) 2 (100%)
 NSAID 34 (9.8%) 13 (11.2%) 13 (10.8%) 3 (15.8%) 4 (15.4%) 2 (5.9%) 1 (4.3%) 0
 Other 31 (9.0%) 8 (6.9%) 10 (8.3%) 0 0 2 (5.9%) 1 (4.3%) 0
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Reactogenicity after vaccine administration occurring within 7 days after each dose in PLWH. Data are n (%). AE, adverse event; NSAID, non-steroidal anti-inflammatory drug; PLWH, people living with HIV.

Fig 4. Severity of adverse events.

Fig 4

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Severity of adverse events present in the 7 days after vaccination in people living with HIV, comparing mRNA (BNT162b2 and mRNA-1273) and vector (ChAdOx1-S and Ad26.COV2.S) vaccines, shown as percentage (%) of participants.

Discussion

Limited data exist on SARS-CoV-2 vaccination responses in PLWH. Here, we show that mRNA induces lower SARS-CoV-2 S1-specific IgG levels in PLWH compared to controls when measured with the LIAISON assay, even after correction for age, sex, and vaccine type. PLWH receiving a vector vaccine, of an older age, and with lower CD4+ T-cell counts have more impaired antibody responses. As expected, the SARS-CoV-2 vaccines were well tolerated in PLWH, without vaccine-related discontinuations or SAEs.

Our primary result analysis in participants receiving mRNA vaccines contrasts with most of the small cohort studies performed in PLWH where the authors found similar responses as in controls [12–14]. With regard to vector vaccines in our study, similar effects were seen as for mRNA vaccines, with lower antibody concentrations in PLWH compared to controls. This differs from previously published results on ChAdOx1-S, where no differences were seen between PLWH and HIV-negative participants [10,11]. Most, if not all, of the previous studies, of both mRNA and vector vaccines, had not been powered to detect a predefined size of impact of HIV on vaccination response. Therefore, this discrepancy is probably a type II error of the previous much smaller studies. Other reasons that may explain why some of the previous studies did not find a lower response in PLWH may be the use of qualitative rather than quantitative antibody responses, showing presence of antibodies rather than magnitude of antibody response. Additionally, these studies included younger participants and a larger percentage of female participants, as well as participants with undetectable viral load and high CD4+ T-cell counts. In contrast to the phase III trials, we observed a lower response in male participants [1,2]. This difference in response between sexes has previously been observed in PLWH, specifically in a yellow fever vaccination study [23]. Additionally, age is also known to influence the immune response to SARS-CoV-2. Our results confirm this in PLWH, in whom more immunosenescence is seen compared to HIV-negative controls [24,25].

Overall, we found an increase in T-cell responses both for activation of CD4+ and CD8+ T-cells and for cytokine production when exposed to SARS-CoV-2 spike protein. There was still a relevant proportion of PLWH in whom T-cell responses after stimulation could not be measured. However, in the AIM assay, this was also observed in controls. Low response or negative responses have also been seen in ELISpot assays performed previously in healthy participants after vaccination [26]. We observed IFN-γ production in both MOG and the medium with DMSO conditions in the PLWH group. This nonspecific spontaneous IFN-γ production by T cells from PLWH could be due to the higher chronic immune activation and persistent inflammation that has been reported before in PLWH [27]. That indeed immune activation leads to higher background spots in ELISpot assays was previously shown in HIV-negative individuals [28].

AEs occurred in just over half of all cases. When looking at BNT162b2, the overall incidence of AEs did not increase after the second vaccination, although the types of AEs differed somewhat (e.g., systemic events occurred more often after the second dose). Overall, AEs in PLWH were mild and similar to those in phase III trials, both in type and frequency [1–3,5].

This study was performed at 22 of a total 24 HIV treatment sites in the Netherlands. Our recruitment strategy resulted in a large group of PLWH, with reasonable representation of female as well as elderly PLWH and those with lower CD4+ T-cell counts. By stratifying at an early stage, we were able to steer inclusion towards more people of certain groups. Our sample reflected the HIV demographics in the Netherlands, in which the 90-90-90 goals were already reached in 2018 [29].

Several limitations are noteworthy. Because provision of vaccinations was decided by the Dutch National Institute for Public Health and the Environment, we could not fully control the distribution of the available vaccines across age, sex, and CD4+ T-cell strata. Furthermore, there were some differences in age and sex between the PLWH and controls, which we corrected for in our multivariate analyses. Few PLWH with a very low CD4+ T-cell count were enrolled, and even fewer with a viral load > 50 copies/mL. We also cannot fully guarantee that all participants with an antecedent COVID-19 infection were excluded as antibodies may become undetectable over time, but no patients in the subgroup study had measurable responses to nucleocapsid. Unfortunately, only a limited number of PLWH could be included in the subgroup study due to the quick start-up of the study and the limited availability of facilities and people to process the samples. However, the characteristics of the participants in the subgroup receiving the mRNA vaccines are comparable to those of the larger group, and we believe to have included enough participants to detect major clinically relevant signals. Finally, we did not perform neutralisation assays. Whilst neutralisation has been shown to correlate with protection against symptomatic infections of SARS-CoV-2, anti-SARS-CoV-2 RBD IgG concentration was shown to strongly correlate with a surrogate virus neutralisation assay after mRNA vaccination [30,31]. Additionally, in a cohort of healthcare workers, spike-specific IgG antibodies strongly correlated with neutralising antibodies [18,32]. In PLWH, neutralisation titres against the Asp614Gly wild-type strain correlated with antibody responses after vaccination with ChAdOx1-S [11].

The COVID-19 landscape continues to change rapidly as new VOCs are emerging. Recent studies have shown immune escape of the Omicron variant from humoral immunity induced by infection as well as vaccination [26]. However, at least in HIV-negative people, an additional vaccine can boost the immune system and restore antibody cross-neutralisation of the Omicron variant [18]. Additionally, higher antibody levels are associated with greater protection against symptomatic disease [33,34]. This highlights the important role that additional vaccinations can play in controlling the pandemic. In these patients, with the vaccines studied, mRNA-based vaccine strategies are to be preferred over vector-based ones. Based on the results of this study, we decided to give all participating PLWH with an antibody response below 300 BAU/mL the opportunity to receive an additional mRNA-1273 vaccination [35]. Furthermore, given the safety of the mRNA vaccines, the overall lower vaccine-inducible antibody response observed in PLWH, the observed waning of serum antibody levels over time, and immune escape by VOCs, we think that providing additional vaccinations to all PLWH may optimise protection. Some recent studies confirm that a third dose in PLWH is beneficial and important in light of more frequent breakthrough infections in PLWH after vaccinations [36,37]. Based on these results, an argument can be made for prioritisation and use of a more targeted approach in, for example, older PLWH, in those with lower CD4+ T-cell counts, or based on measured antibody responses and neutralisation capacity after vaccination. Whilst this argument can be made in the case of resource-limited settings, or when prioritisation of vaccination is a requirement, we do not believe this is necessary when vaccinations are freely available. Additionally, this is not a practical approach in the case of limited availability of human resources or of SARS-CoV-2 antibody assays, or where CD4+ T-cell counts are not easily performed.

In conclusion, vaccination of PLWH against SARS-CoV-2 resulted in a lower antibody response compared to HIV-negative controls. Additional vaccinations may therefore be required in order to compensate for this reduced antibody response.

Supporting information

S1 Fig. Gating strategy for flow cytometry in AIM assay.

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S2 Fig. Serological responses after vaccination in PLWH.

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S3 Fig. Cellular immune responses against SARS-CoV-2 in subgroup participants (PLWH).

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S4 Fig. ELISpot results in subgroup participants (PLWH).

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S1 STROBE Checklist

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S1 Table. Baseline characteristics of HIV-negative participants and PLWH by vaccine.

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S2 Table. Subgroup patient characteristics.

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S3 Table. Regression model to investigate the difference in antibody concentration between PLWH and HIV-uninfected controls vaccinated with 1 of the 2 available mRNA vaccines (BNT162b2 or mRNA-1273).

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Click here for additional data file. (29.1KB, docx)
S4 Table. HIV-related and HIV-unrelated factors associated with the height of antibody response after vaccination with 1 of the 2 available mRNA vaccines (BNT162b2 or mRNA-1273) in PLWH.

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Click here for additional data file. (29.5KB, docx)
S5 Table. Regression model to investigate the difference in antibody concentration between PLWH and HIV-uninfected controls vaccinated with 1 of the 2 vector vaccines (ChAdOx1-S or Ad26.COV2.S).

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Click here for additional data file. (29.1KB, docx)
S6 Table. HIV-related and HIV-unrelated factors associated with the height of antibody response after vaccination with 1 of the 2 vector vaccines (ChAdOx1-S or Ad26.COV2.S) in PLWH.

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Click here for additional data file. (29.6KB, docx)
S7 Table. Linear regression model to investigate factors associated with the antibody response after completion of the vaccination schedule in PLWH with antibody concentration above the minimal level of clinical protection (≥300 BAU/mL).

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Click here for additional data file. (29.5KB, docx)
S8 Table. Linear regression model to investigate factors associated with the antibody response after completion of the vaccination schedule in PLWH with a quantifiable antibody concentration (≥33.8 BAU/mL).

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S1 Text. Additional information on study design and participants.

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S2 Text. Additional information on ELISpot assay.

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S3 Text. Additional information on AIM assay.

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Acknowledgments

Foremost, we would like to thank all participants of the study for helping advance science. We also want to thank the following people who helped in the recruitment of participants: Aniek Adams, A. Boonstra, Marjolein van Broekhuizen, Margo van der Burg-van der Plas, A. Cents-Bosma, Willemien Dorama, T. Duijf, S. Faber, Natasja van Holten, Astrid van Hulzen, L. M. Kampschreur, Annemarie van der Kraan, Inge de Kroon, Laura Laan, Eliane Leyten, Vera Maas, P. A. der Meulen, Femke Mollema, Suzanne de Munnik, Hans-Erik Nobel, Vincent Peters, Simone Phaf, M. Pietersma, Frank Pijnappel, Leontine M. M. van der Prijt, Linda Scheiberlich, Jasmijn Steiner, Jolanda M. van der Swaluw, Maartje Wagemaker, Annouschka Weijsenveld, Marc van Wijk, Sieds Wildenbeest, and Sabine van Winden. We would like to thank all our colleague internist–infectious disease specialists in the Netherlands who helped with the patient recruitment. Finally, we would like to thank Alessandro Sette and Alba Grifoni (La Jolla Institute for Immunology, La Jolla, San Diego, US) for providing the peptide pools used in the AIM assay.

Abbreviations

AE

adverse event

AIM

activation-induced marker

BAU

binding antibody units

cART

combination antiretroviral therapy

DMSO

dimethyl sulfoxide

ELISpot

enzyme-linked immune absorbent spot

GMC

geometric mean concentration

MOG

myelin oligodendrocyte glycoprotein

OR

odds ratio

PBMC

peripheral blood mononuclear cell

PLWH

people living with HIV

SAE

serious adverse event

SFC

spot-forming cell

VOC

variant of concern

Data Availability

Individual participant data that underlie the results reported in this article, after de-identification, will be made available to researchers who provide a methodologically sound study proposal. Requests for the data on PLWH can be made to the Erasmus MC HIV Eradication Group (EHEG) at eheg@erasmusmc.nl. Contact for inquiries data healthy controls: VACOPID COVID-19 vaccination study: L.P.M. (Leanne) van Leeuwen (l.p.m.vanleeuwen@erasmusmc.nl) and Health Care Workers cohort Erasmus MC: M.C. (Marc) Shamier (m.shamier@erasmsumc.nl).

Funding Statement

This trial was funded by The Netherlands Organization for Health Research and Development (ZonMw) (10430072010008 to KB). Control samples were obtained from the VACOPID study, funded by ZonMw (10430072010006 to VASHD and RdDV). DG and RDdV are supported by the Health~Holland grant co-funded by the PPP Allowance made available by the Health~Holland, Top Sector Life Sciences & Health, to stimulate public –private partnerships (EMCLHS20017 to DG and RDdV). https://www.zonmw.nl/en/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Beryne Odeny

29 Mar 2022

Dear Dr Hensley,

Thank you for submitting your manuscript entitled "Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV: a nationwide prospective cohort study in the Netherlands" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Mar 31 2022 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Beryne Odeny

PLOS Medicine

Decision Letter 1

Beryne Odeny

1 Jun 2022

Dear Dr. Hensley,

Thank you very much for submitting your manuscript "Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV: a nationwide prospective cohort study in the Netherlands" (PMEDICINE-D-22-01021R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

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Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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We look forward to receiving your revised manuscript.

Sincerely,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Comments from Academic editor

I would have preferred to see data presented on neutralizing antibodies as well since that is regarded as the major mediator of protection. However, the authors argument that neutralizing Abs have been shown to correlate with IgG titres is a reasonable point. As an alternative, the authors could consider including data generated using a surrogate ELISA-based neutralization assay which is available commercially and suitable for testing large number of samples without specialised culture facilities. I would also like to have seen a little more analysis of differences in Abs between HIV+ vs HIV-, such as IgG subclasses which are relevant in immunity and can be impacted by HIV.

Requests from the editors:

1) Please revise your title: Please place the study setting before the colon. For example, “… in the Netherlands: a

nationwide prospective cohort study”

2) The Data Availability Statement (DAS) requires revision. For each data source used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

3) Abstract:

a) Abstract Background: The final sentence should clearly state the study question.

b) Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

c) Please include the actual amounts and/or absolute risk(s) of relevant outcomes

d) Please quantify the main results (please present both 95% CIs and p values).

e) In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

4) Author summary - At this stage, we ask that you reformat your non-technical Author Summary. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. The summary should be accessible to a wide audience that includes both scientists and non-scientists. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary.

5) Please conclude the Introduction with a clear description of the study question or hypothesis.

6) Methods:

a) Please report the number of patients and samples, and dates of recruitment

b) Please report how many patients were "lost to follow-up" as used in this study.

7) Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

a) Thank you for providing the STROBE checklist. When completing the checklist, please use section and paragraph numbers, rather than page numbers.

8) Please provide p values in addition to 95% CIs in the main text and tables

9) Please indicate in the figure captions the meaning of the bars and whiskers in figure 2, S3

10) Please use up to 3 decimal points for p-values

11) Please define all abbreviations used in footnotes of tables and figures

12) Please replace "subject" with participant, patient, individual, or person.

13) Please replace “HIV patients” with “people living with HIV”

14) Please re-label the Conclusion section to Discussion.

15) Please organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

16) References: Please include access dates for all weblinks and ensure that all weblinks are current and accessible e.g ref # 28

17) We suggest you copyedit your manuscript for language usage, spelling, and grammar.

Comments from the reviewers:

Reviewer #1: This prospective cohort study aims to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S and 57 Ad26.COV2.S vaccines in adult PLWH, without prior COVID-19, compared to HIV-negative controls.

Comments:

"Between February-September 2021, 1154 PLWH (median age 53 [IQR 44-60], 86% male) and 440 controls (median age 43 [IQR 33-53], 29% male) were included."

and

"We performed a prospective observational cohort study in 22 of the 24 HIV treatment centres in the Netherlands."

and

"Inclusion was stratified and monitored to best represent represents the Dutch population of PLWH (S1 appendix)"

Can the authors please provide further information on this stratification process? Did the authors consider including any stratification variables within the analysis?

Additionally, can the authors comment on whether the stratification and monitoring they completed was successful (i.e. do the authors consider the analysed sample to be representative of the wider population)?

"Blood samples were collected up to six weeks before vaccination (T0) and four to six weeks after the completed vaccination schedule (T2)."

Did the authors consider including time to sample collection (after completed vaccination schedule) as a covariate in the analysis?

"In a subgroup, additional blood samples were collected, 21 days (+/- three days) after the first vaccination for serology (T1) or peripheral blood mononuclear cells (PBMCs) at any of the study visits."

Can the authors please provide further information here? For instance, can the authors please specify in the Methods the number of participants included in these subgroups, and how the participants were selected (e.g. randomly)?

"ELISpot T0 to T2 data and AIM data comparing PLWH and controls were analysed by Mann-Whitney-U tests."

S2 table shows these subgroups, and it can be seen that there are no HIV negative controls over 65 years of age. Did the authors consider including covariates in this analysis?

Can the authors please discuss the small sample sizes included for these subgroup analyses?

"We justified the sample size by calculating that 556 PLWH receiving mRNA vaccines would be sufficient to detect a serological response rate of 90% or lower compared to a hypothetical 95% response rate in controls with >80% power. When the control group was confirmed, and before the data lock and endpoint analyses, we amended the protocol to update the sample size calculation. Accounting for the imbalance in the number of controls versus PLWH with BNT162b2 and mRNA-1273 vaccinations, we found that 286 controls were sufficient to detect a 20% lower antibody response in PLWH with >80% power and alpha 5%."

The authors suitably provide the basis of the sample size calculations, and associated assessment of study power.

"Median (interquartile range (IQR)), or n (%) for descriptive data were used. A multivariable linear regression model was used for the analysis of the anti-spike SARS-CoV-2 IgG. The outcome was transformed using the natural logarithm plus one unit: ln(anti-spike SARS-CoV-2 IgG+1) in order to meet the model assumptions. "

and

"In subgroup participants we evaluated differences from baseline to T1 and T1 to T2, as well as AIM data comparing T0 and T2 time points, by Wilcoxon matched-pairs signed rank test."

Technically appropriate statistical techniques and modelling methods have been applied by the authors within the context of this research.

"The model was further adjusted for differences in vaccine type, age, and sex. A multivariable linear regression model was also used to quantify the difference in ln(anti-spike SARS-CoV-2 IgG+1) between PLWH versus controls for the subset in the sample vaccinated with vector vaccines. A similar model was used to quantify the effect of age, sex, vaccine type, most recent CD4+ T-cell count, and antibody concentration in PLWH. In addition, multivariable logistic regression models were used to calculate odds ratios with 95%CI for the effects of sex, age, nadir CD4+ T-cell count, most recent CD4+ T-cell count, HIV-RNA viral load, and vaccine group in PLWH on having a hyporesponse or a non response."

Do the authors have information on ethnicity, BMI, or comorbidities that they can consider including in these models?

Table 1: Did the authors consider treating age as a continuous variable?

Did the authors consider including days between doses as a covariate in the models?

Can the authors also please present the fully adjusted models in the tables and figures?

Reviewer #2: Hensley et al. have performed a large-scale study of people living with HIV (PLWH) and their response to a variety of covid19 vaccines. The size of the study is a major strength. The clearest findings from the manuscript are a lower binding antibody response in PLWH compared to controls and a large alteration in binding titres dependent on vaccine type. They do not evaluate antibody neutralisation activity (understandably given the number of samples) nor attempt to relate their binding data to previous studies exploring the relationship between binding/neutralisation titres and vaccine efficacy. Greater discussion of how these binding data fit in the wider cannon of Covid19 vaccine studies (including but not limited to those with PLWH) is needed to make this manuscript of publication quality, please see individual critiques.

The authors do assess cellular immune responses in a sub-group of individuals. However, this data is not particularly clear as the negative control stimulation (an MS associated peptide pool) appears to give a very high response in PLWH. This portion of the data as it currently stands is very confusing and not particularly informative, please see queries below.

Individual critiques

Line 58: The authors state that "the primary endpoint of their study was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination". This is perfectly reasonable, but please acknowledge clearly in the manuscript that neutralisation titres, not just total IgG binding titre, are likely important for vaccine efficacy and that neutralisation hasn't been measured here

Line 67-67: Please make it clear if any participants don't seroconvert and what % this is.

Line 76-77: "To reach and maintain the same serological responses and vaccine efficacy as HIV-negative controls, additional vaccinations are probably required."

This statement needs to be properly caveated as this study has not directly addressed vaccine efficacy nor explored links between the titres measured/serological differences observed and vaccine efficacy.

Line 87-89: "After the SARS-CoV-2 vaccine registration trials, vaccinations were rolled out globally. However, people

with immune deficiencies were only sporadically included in the original phase three SARS-CoV-2 vaccination trials."

Please add details of PLWH included - numbers / % as appropriate

Line 89-91: "Subsequent reports indicated markedly diminished responses in solid organ transplant recipients, and lower responses in haemodialysis patients, stem cell recipients or patient groups on specific immunosuppressant drugs for immune disorders [6-9]."

Please include the magnitudes of these lower responses to put your findings here into context.

Line 97-98: "that after SARS-CoV-2 infection, lower IgG concentrations and neutralising antibody titres were found in PLWH compared to controls [13]"

There are other studies where this was not found, and these should also be cited.

Line 103-4: "A good understanding of vaccination response in PLWH becomes even more important now that variants of concern (VOC) continue to arise and partially escape vaccine induced immunity [19]."

Should be mentioned that persistent infection in PLWH is also a plausible mechanism for generation of VOC (there are at least 2 papers/pre-prints from South African groups on this)

Line 138: "validated IgG Trimeric chemiluminescence immunoassay (DiaSorin Liaison)"

Please provide information on how this assay performs with either of the WHO standards or how results can be converted?

Line 147: Please define MOG at first use.

Line 155 & 159: Please change height to magnitude.

Line 161: "hyporesponse as 50-300 BAU/mL and non-response as <50 BAU/mL, based on previous studies"

If non-response equates to seronegative, please use that term.

Line 204: "At sampling before vaccination, 53 (4.2%) PLWH had antibodies against SARS-CoV-2 above test cut-off and were excluded."

Please state if these were antibodies against N or S?

Line 234: "In all vaccines investigated, antibody concentrations were lower in PLWH compared to controls (Fig 2)."

Please state this after 2 vaccine doses

Fig 2: Antibody concentration in PLWH and controls after vaccination

The results in this figure are intriguing and given the high numbers of samples tested please comment on whether this study is adequately powered to say which vaccine PLWH should have given the defect observed between vaccine types.

Line 254: "We found no association between nadir CD4+ T-cell count and antibody responses"

Since Ab response in PLWH have such a different spread especially after bnt162b2, please make a correlation plot to visualize what kind of clinical parameters the people with Ab <300BAU/ml. Even if there is no correlation, seeing the data this way would be informative.

Line 259: "over 500 cells/μL (2.936 95%CI 1.961-4.394) (both

259 p<0.001) with increased antibody concentrations of 184.34% and 193.59% respectively."

Increased compared to what? people with CD4 count under 200? Please clarify.

Line 266: please call "non-response" seronegative unless there is some reason to believe this assay has an artificially high limit of detection

Line 273-6: "Being 56 to 65 years of age (p=0.025, OR 2.919) and most recent CD4+ T-cell count between 250 and 500 cells/μL or over 500 cells/μL (both p<0.001 OR 7.810 and 15.853 respectively) were significantly associated with an antibody response of more than 50 BAU/mL. Sex, viral load and nadir CD4+ T-cell count were not associated."

What about associations with being off treatment/ blips/ poor adherence or treatment type?

Line 285:

Firstly, it should be clearly explained here why nucleocapsid responses are looked at and why MOG is used as a negative control.

Secondly, the MOG responses in FigS3 are almost as big as the responses shown in S3 thus the subtraction does not make much sense. There seems to be some technical issue that has not been well described here so it's impossible to assess the value of these data. If the S3 is accurate then there is a negative control MOG response of equivalent magnitude to the Spike specific response, both before AND after vaccination. This doesn't make sense. If PLWH have an oddly higher reactivity against MOG then unstimulated control would be a better comparator. Was an unstimulated control performed? Can this data be included used to perform the subtraction instead?

Fig 3: Cellular immune responses against SARS-CoV-2 in subgroup participants (PLWH)

There's no real indication in the data in this figure that cellular responses are worse in PLWH as claimed in conclusion

Fig 3.A

It would be clearer to have one graph for mRNA vaccines and one graph for vectored vaccines. Please indicate how many people have a neg response at T0 and T2. Consider replacing T0/T2 nomenclature by actual baseline/post 2 doses as this is more intuitive for the reader.

Fig 3.B

Why in the left-hand panel isn't the delta response increasing with vaccination? this is whole spike peptide pool. Data so far from others shows no real alteration in WT vs VOC T cell ELISpot unless just a mutation specific pool is used. So, this seems wrong.

Line 340: "Limited data exist on SARS-CoV-2 vaccination responses in PLWH."

This is true, but there is some data in publicly available studies, and these should be cited and mentioned here to put this work into context

Line 341: "lower SARS-CoV-2 S1-specific IgG levels in PLWH compared to controls"

Should add "as measured by diasorin assay" it's important to stress how this result was found as it is different to other studies to date.

Line 345-6: "Our primary result analysis in participants receiving mRNA vaccines contrasts with most of the small cohort studies performed in PLWH where the authors found similar responses as in controls [16-18]."

This is a major finding and so the authors should expand further on why this difference is found.

Line 350: "Most, if not all, of the previous studies had not been powered to detect a predefined size of the impact of HIV on vaccination response"

Again, here there needs to be a discussion around the fact that binding not being the be all and end all of serology and that neutralisation has not been assessed.

Line 352: "Other reasons that may explain why some of the previous studies did not find a lower response in PLWH may be the use of qualitative rather than quantitative antibody responses"

Please expand on why these results are quantitative whereas prior studies are qualitative - this doesn't seem correct (or at least intuitive) to this reviewer.

Line 355: "However, this was observed in other vaccination studies in PLWH previously [23]"

Please highlight you mean against other pathogens

Line 357: "Our results confirm this in PLWH, in whom more immunosenescence is seen compared to HIV-negative controls [24, 25]."

Please discuss in text whether this means you are seeing these differences because cohort of PLWH contained more old people compared to other cohorts?

Line 363: "We observed a relevant IFN-γ production in the negative control stimulation in the PLWH group."

I don't understand this sentence and I don't see the data supporting this in the figures.

Line 384: "However, at least in HIV-negative people, this can be overruled by a booster vaccination [21]."

Overruled is not the right word for this context… and can a booster fix everything? I think there needs to be more discussion about what these differences might mean for clinical vaccine efficacy and whether extra boosters or higher doses/altered regimen is needed (as per some other vaccines in PLWH)

Reviewer #3: In this work, Hensley et al. present the data from over 1154 people living with HIV/AIDS (PLWHA) and 884 controls who were vaccinated for Covid-19 to explore the anitgen-specific humoral and celluar immune responses. This is a multi-site study, involving 22 out of 24 centers providing care to PLWHA in The Netherlands.

Their findings line up with findings from other groups, suggesting that the vaccines are immunogenic and well tolerated in PLWHA. They also expand to a more detailed data on the celluar immune response, which is a strong point, despite the number of analyzed subjects.

The results adds, in a compreehensive observation, the need to vaccinate PLWHA for Covid-19. Although no efficacy data is presented and one still lack the marker of protection for the disease, this is important information to be generated and communicated.

Minor comment:

1. Authors should acknowledge findings with other vaccine platforms, including inactivated virus

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Beryne Odeny

26 Jul 2022

Dear Dr. Hensley,

Thank you very much for submitting your manuscript "Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: a nationwide prospective cohort study" (PMEDICINE-D-22-01021R2) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Aug 16 2022 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

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PLOS Medicine

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Comments from the Academic editor:

Just noting that in the legend of Fig 2 the authors need to state the p values (and test used) for comparisons between HIV- and PLWH, and how many subjects in each group (they have included this information in the Figure 3 legend). And also state what the numbers above the dot-plots represent.

Comments from the reviewers:

Reviewer #1: Many thanks to the authors for satisfactorily considering and responding to each comment in turn, amending the manuscript where necessary.

Reviewer #2: The major original critique was that the T cell component was confusing. This has not been well-addressed. It is still unclear if the spike SFU numbers shown in FigS4 have already had the background subtracted or not, I would strongly suggest DMSO subtraction is more comparable to other studies than MOG subtraction. The data in FigS3 look as expected but it doesn't make sense how they are derived from the data in FigS4 as the Spike responses are equal in magnitude to the DMSO/MOG/NC in Fig4S? And the DMSO responses are abnormally large. This is very different to other studies where spike-specific responses are much larger than DMSO - this is how we know the assay has actually worked when running them. Based on the data presented I cannot support their publication as I am concerned there is an artefact, in my view these data should be removed as the serology is valid independently.

The issue of referring to a non-response rather than seronegative has not been resolved, I think this would be clearer for the wider community doing a variety of assays not just this specific one. Also, they refer to clinical expertise in drawing the line at 50 BAU/ml where the manufacturer says 33.8 BAU/ml. I understand views on what is a "useful" response may be taken in a clinical setting but it doesn't make clear sense to me in a research paper to disregard manufacturers guidelines on cut-offs based on sensitivity and specificity data using known positive and negative cases that enabled clinical use of the assay in the first place and call this "non-response". Moreover, the term "adequate response" for >300 BAU/ml is misleading as it implies some knowledge of how this assay relates to protection which has not been explored here. I would strongly suggest using the term "normal" rather than "adequate".

The new Author summary also has a major issue in the following claim:

" Because the height of the antibody response correlates with protection against symptomatic infection"

This paper does not look at protection in anyway, so it is not a good idea to make this claim here. If there are papers to support that binding responses (especially this particular assay and the cut offs used by these investigators) correlate with protection from symptomatic infection, then these should be discussed in the discussion and not presented as a key finding /outcome of this piece of work in the author summary. The discussion presents a set of studies linking various parameters to one another but not the direct link of binding to protection, and importantly not the magnitude of binding response in this assay to protection so do not support this statement, and regardless I don't think it belongs in the Author Summary as it is not one of their findings.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Beryne Odeny

12 Sep 2022

Dear Dr. Hensley,

Thank you very much for re-submitting your manuscript "Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: a nationwide prospective cohort study" (PMEDICINE-D-22-01021R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by one reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Sep 19 2022 11:59PM.   

Sincerely,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1) The Data Availability Statement (DAS) requires revision for each data source used in your study. If the data are not freely available, please include an appropriate contact (web or email address) for inquiries (this cannot be a study author).

2) In the supplementary files, please indicate p <0.001 instead of p = 0.000

Comments from Reviewers:

Reviewer #2: Acceptable clarifications have now been made to the T cell part of the story.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 4

Beryne Odeny

20 Sep 2022

Dear Dr Hensley, 

On behalf of my colleagues and the Academic Editor, Dr. James G. Beeson, I am pleased to inform you that we have agreed to publish your manuscript "Immunogenicity and reactogenicity of SARS-CoV-2 vaccines in people living with HIV in the Netherlands: a nationwide prospective cohort study" (PMEDICINE-D-22-01021R4) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Beryne Odeny 

PLOS Medicine

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Gating strategy for flow cytometry in AIM assay.

    (DOCX)

    Click here for additional data file. (322.1KB, docx)
    S2 Fig. Serological responses after vaccination in PLWH.

    (DOCX)

    Click here for additional data file. (204.3KB, docx)
    S3 Fig. Cellular immune responses against SARS-CoV-2 in subgroup participants (PLWH).

    (DOCX)

    Click here for additional data file. (214.3KB, docx)
    S4 Fig. ELISpot results in subgroup participants (PLWH).

    (DOCX)

    Click here for additional data file. (210KB, docx)
    S1 STROBE Checklist

    (DOCX)

    Click here for additional data file. (36.8KB, docx)
    S1 Table. Baseline characteristics of HIV-negative participants and PLWH by vaccine.

    (DOCX)

    Click here for additional data file. (19KB, docx)
    S2 Table. Subgroup patient characteristics.

    (DOCX)

    Click here for additional data file. (31.9KB, docx)
    S3 Table. Regression model to investigate the difference in antibody concentration between PLWH and HIV-uninfected controls vaccinated with 1 of the 2 available mRNA vaccines (BNT162b2 or mRNA-1273).

    (DOCX)

    Click here for additional data file. (29.1KB, docx)
    S4 Table. HIV-related and HIV-unrelated factors associated with the height of antibody response after vaccination with 1 of the 2 available mRNA vaccines (BNT162b2 or mRNA-1273) in PLWH.

    (DOCX)

    Click here for additional data file. (29.5KB, docx)
    S5 Table. Regression model to investigate the difference in antibody concentration between PLWH and HIV-uninfected controls vaccinated with 1 of the 2 vector vaccines (ChAdOx1-S or Ad26.COV2.S).

    (DOCX)

    Click here for additional data file. (29.1KB, docx)
    S6 Table. HIV-related and HIV-unrelated factors associated with the height of antibody response after vaccination with 1 of the 2 vector vaccines (ChAdOx1-S or Ad26.COV2.S) in PLWH.

    (DOCX)

    Click here for additional data file. (29.6KB, docx)
    S7 Table. Linear regression model to investigate factors associated with the antibody response after completion of the vaccination schedule in PLWH with antibody concentration above the minimal level of clinical protection (≥300 BAU/mL).

    (DOCX)

    Click here for additional data file. (29.5KB, docx)
    S8 Table. Linear regression model to investigate factors associated with the antibody response after completion of the vaccination schedule in PLWH with a quantifiable antibody concentration (≥33.8 BAU/mL).

    (DOCX)

    Click here for additional data file. (29.7KB, docx)
    S1 Text. Additional information on study design and participants.

    (DOCX)

    Click here for additional data file. (28.4KB, docx)
    S2 Text. Additional information on ELISpot assay.

    (DOCX)

    Click here for additional data file. (28.4KB, docx)
    S3 Text. Additional information on AIM assay.

    (DOCX)

    Click here for additional data file. (28.6KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (106.3KB, docx)
    Attachment

    Submitted filename: Response to reviewers - second revision.docx

    Click here for additional data file. (142.9KB, docx)
    Attachment

    Submitted filename: Response to reviewers - final.docx

    Click here for additional data file. (90.4KB, docx)

    Data Availability Statement

    Individual participant data that underlie the results reported in this article, after de-identification, will be made available to researchers who provide a methodologically sound study proposal. Requests for the data on PLWH can be made to the Erasmus MC HIV Eradication Group (EHEG) at eheg@erasmusmc.nl. Contact for inquiries data healthy controls: VACOPID COVID-19 vaccination study: L.P.M. (Leanne) van Leeuwen (l.p.m.vanleeuwen@erasmusmc.nl) and Health Care Workers cohort Erasmus MC: M.C. (Marc) Shamier (m.shamier@erasmsumc.nl).

    Articles from PLOS Medicine are provided here courtesy of PLOS

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