One-month humoral response following two or three doses of mRNA Covid-19 vaccines as primary vaccination in specific populations in France: first results from the ANRS0001S COV-POPART cohort.

OBJECTIVES: We aimed to investigate the one-month humoral response to two or three doses as primary vaccination in specific populations compared to healthy adults.
METHODS: ANRS0001S-COV-POPART (NCT04824651) is a French nationwide multicenter prospective observational cohort study assessing the immune response to Covid-19 vaccines routinely administered to 11 subgroups of patients with chronic conditions and two control groups. Patients and controls who had received at least two vaccine doses and whose results at one month after the second dose were available have been included. Humoral response was assessed at 1-month post first dose, post second dose and post third dose (if applicable), through the percentage of responders (positive anti-Spike SARS-CoV-2 IgG antibodies, geometric means of anti-Spike SARS-CoV-2 IgG antibodies (ELISA) and proportion of participants with anti-SARS-CoV-2-specific neutralizing antibodies (in vitro neutralization assay for the original SARS-CoV-2 strain). All analyses were centralized.
RESULTS: We included 4091 participants in this analysis: 2979 participants from specific subpopulations and 1112 controls. Only 522 (17.5%) of the specific populations received 3 doses as primary vaccination regimen. Patients living with HIV, cancer and diabetic patients had high rates of responders after two doses while solid organ transplant (SOT), allogeneic hematopoietic stem cell transplant (HSCT) and hypogammaglobulinemic patients had the lowest percentage of responders (35.9% [95%CI: 29.2; 43.0], 57.4% [48.1; 66.3]) and 77.1% [65.6; 86.3] respectively). In those who received a third dose, the rate of responders reached 54.2% [42.9-65.2] (vs. 32.3% (16.7-51.4) after 2 doses) in SOT and 73.9% [58.9-85.7) (vs. 56.1% [46.2-65.7] after 2 doses) in HSCT. Similar results were found with anti-SARS-CoV-2-specific neutralizing antibodies.
CONCLUSIONS: Lower COVID-19 vaccine humoral response was observed in specific populations compared to controls. A third dose of vaccine in the primary regimen had a positive effect on both percentages of patients who developed anti-Spike IgG antibodies and specific neutralizing antibodies.

Introduction

Specific populations such as immunocompromised or obese patients are defined as individuals at risk of developing severe forms of infectious diseases and in whom there are concerns of potentially decreased immunogenicity and effectiveness of vaccines. Covid-19 vaccines phase 3 studies provide little information on vaccine efficacy in specific populations. First real-life studies showed lower anti-Spike antibody responses [1,2] leading to lower vaccine efficacy compared to non-immunocompromised populations [3, 4, 5, 6]. Most of these studies were based on small sample sizes, no standardized measure and without control groups [1,2]. Many countries have recommended at least one additional dose in primary vaccination regimen in immunocompromised populations with convincing results on humoral response in small studies [7].

Detailed short- and long-term immune response assessment in these populations according to the number of doses of vaccine received are warranted to inform reflections on tailored vaccine regimen.

The ANRS0001S COV-POPART cohort study aims at assessing humoral immune responses to Covid-19 vaccines in 11 subgroups of specific populations compared to a control group [8].

Methods

Study design and patients

ANRS0001S-COV-POPART (NCT04824651) is a multicenter prospective cohort study conducted in France assessing the immune response to Covid-19 vaccines routinely administered to specific populations as part of the national immunization campaign [8].

The study was conducted in 36 participating centres in France in collaboration with the I-reivac network, ten national learned societies and seven patients’ associations (France Rein – Transhépate – ARSEP Foundation – CNAO – FFD – EGMOS – TRT5 CHV).

Adults without known history of Covid-19 and affected by one of the following chronic diseases: solid cancer, solid organ transplant (SOT), allogeneic hematopoietic stem cell transplant (HSCT), chronic renal failure (stage 4 and 5 = GFR < 30 mL/min/1.73m2) with or without dialysis, multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), inflammatory rheumatic diseases (IRD), systemic autoimmune diseases (SAD), hypogammaglobulinemia (primary and secondary), obesity (BMI > 30 kg/m2), diabetes mellitus (both type 1 and 2) or patients living with HIV (PLWHIV) and willing to be vaccinated as part of the national immunization campaign have been included from March 25th, 2021 to December 31st, 2021. Patients might have been included before any vaccination, after the first dose or in the month following the second dose. Patients could be affected by more than one chronic condition and thus included in different specific populations. In this study, they will be described in each of their population of inclusion.

One control group without any of the above-mentioned underlying conditions has also been set-up. This control group was initially stratified in two groups below 75 and >=75. However, the recruitment in the >=75 group was not successful. For statistical analyses we considered participants <65 and >=65.”

Main exclusion criteria were pregnancy or breastfeeding, history of known SARS-CoV-2 infection, acute febrile infection within the previous 72 h, symptoms suggestive of Covid-19 or contact with a case within the last 14 days prior to the inclusion visit, history of severe post-vaccination adverse events or severe allergic manifestations, having received another vaccine within 4 weeks prior to the first injection or scheduled to receive a licensed vaccine in the 4 weeks following inclusion.

Patients and controls who had received at least two doses of mRNA vaccine (i.e patient who received one dose of Covid-19 Vaccine Janssen or heterologous vaccination regimen such as ChAdOx1-nCoV19/BNT162b2 were excluded) and whose results at one month after the second dose were available have been included. Furthermore, participants with positive SARS CoV-2 anti-nucleocapsid (NCP) antibodies pre-vaccination or at any follow-up visit were excluded.

Details on Covid-19 vaccination are available in Supplementary materials.

Samples collection and laboratory assays

Serum samples were collected at inclusion, 1 month post dose 1, 1 month post dose 2, 1 month post dose 3 (if applicable) for this analysis. Data collected between 21 and 56 days after the injection were considered as measured one month post dose. Samples collected at each site were sent to a certified core laboratory (CRB Bordeaux) before being sent for serological analysis to the “Unité des virus émergents” Aix-Marseille Université, Institut de Recherche pour le Développement 190, Inserm 1207, Institut Hospitalo-Universitaire Méditerranée Infection – Marseille, France.

Details on laboratory assay are available in Supplementary materials.

Outcomes

The main outcome measures were the percentage of responders (positive anti-Spike SARS-CoV-2 IgG antibodies (ELISA), ≥ 1.1 ratio of the optic density between sample and calibrator, as defined by EuroImmun serology), geometric means titers of anti-Spike SARS-CoV-2 IgG antibodies expressed in BAU/mL, and anti-SARS-CoV-2-specific neutralizing antibodies (in vitro neutralization assay for the original SARS-CoV-2 strain) at 1 month (21 to 56 days) after last dose of the primary vaccination regimen (two or three doses). Quantitative distributions were described only in responders’ participants for this antibody. Responders were categorized in weak (anti-Spike SARS-CoV-2 IgG level < 264 BAU/mL)[10] moderate ([264 and 1350[ BAU/mL) and strong responders (>1350 BAU/mL, corresponding to the median IgG anti-Spike level observed in all controls).

Proportion of participants with seroneutralisation antibodies (a titer above or equal to 20) were described by percentages.

Details on statistics are available in Supplementary materials.

Ethics

Written informed consent was obtained from each participant before enrolment taking into account the GDPR (European Union General Data Protection Regulation) requirements. The protocol (N° EudraCT/ID-RCB: 2021-A00348-33) was conducted in accordance with the Declaration of Helsinki and French law for research involving human subjects (known as Loi Jardé). The protocol was approved by Ethics Committees: the committee for protection of persons engaged in research “CPP Nord-Ouest IV”(file number: 21.02.12.47147) and the French national data protection authority “CNIL” (Commission Nationale Informatique et Liberté, authorization number 921111v1).

Results

Patients

Of the 6108 participants recruited until December 31st 2021, 4348 (71%) had available 1-month post second dose of the primary vaccination regimen results at the time of the first analyses, among whom 4091 (67%) had no anti-NCP antibodies: 2979 participants from specific subpopulations and 1112 controls (See Flow chart Supplementary Figure 1). Details on the number of patients included in each subpopulation are displayed in Table 1 . Details on the characteristics of the participants included in each subpopulation are displayed in Supplementary Tables 1 to 11. The overall median age was 51.1 years [InterQuartile range: 40.3 – 60.4] and 2047 (50.0%) were Male. Most participants received at least two doses of the BNT162b2 vaccine (3581, 87.5%). Among the specific populations, 522 (17.5%) patients received 3 doses as primary vaccination regimen, most of them were HSCT (n=107, 87.7% of this sub-population) and SOT (n = 167, 84.3% of this sub-population). Median time between second and third dose was 4.1 weeks [4.0 – 4.9]. HSCT patients who received 3 doses were older (54.7 [39.5-65.6] vs 52.5 [41.0-56.5]), and more likely to have received the allograft less than three years (94.2% vs 60.0%) than those who received only 2 doses. SOT patients who received 3 doses were older (58.3 [48.0-66.4] vs 56.6 [47.8-65.6]), had received T-cell-depleting agents more recently and were more likely to be other organ (heart, lung, liver, pancreas) than kidney recipients than those who received only 2 doses.

Table 1

Characteristics of patients and controls included in the preliminary analyses of the ANRS0001 S COV-POPART cohort study

Characteristics	Specific population (n = 2979)		Control group < 65 years (N= 962)		Control group ≥ 65 years (N= 150)
	N	Median [IQR] or n (%)	N	Median [IQR] or n (%)	N	Median [IQR] or n (%)
Age (years)	2974	52.5 [41.9; 61.3]	962	43.9 [34.1; 52.1]	150	70.8 [68.1; 74.7]
Men	2979	1504 (50.5)	962	473 (49.2)	150	70 (46.7)
Population	2979		-		-
Cancer		188 (6.3)		-		-
Solid organ transplant		198 (6.6)		-		-
Hematopoietic stem cell transplant		122 (4.1)		-		-
Chronic renal failure with or without dialysis		95 (3.2)		-		-
Systemic autoimmune diseases		173 (5.8)		-		-
Inflammatory rheumatic diseases		191 (6.4)		-		-
Multiple sclerosis/neuromyelitis optica spectrum disorders		416 (14.0)		-		-
Hypogammaglobulinemia		70 (2.3)		-		-
Diabetic		445 (14.9)		-		-
Obese non-diabetic		820 (27.5)		-		-
HIV patients		897 (30.1)		-		-
Type of vaccine	2919		955		149
BNT162b2+ BNT162b2		2163 (74.1)		854 (89.4)		138 (93.3)
BNT162b2 + BNT162b2 + BNT162b2		426 (14.6)		-		-
mRNA-1273 + mRNA-1273		230 (7.9)		92(9.6)		10 (6.7)
mRNA-1273 + mRNA-1273 + mRNA-1273		78 (2.7)		-		-
BNT162b2 + mRNA-1273		15 (0.5)		9 (0.9)		0 (0.0)
BNT162b2 + BNT162b2 + mRNA-1273		3 (0.1)		-		-
BNT162b2 + mRNA-1273 + mRNA-1273		4 (0.1)		-		-
Number of doses	2979		962		150
2		2457 (82.5)		962 (100.0)		150 (100.0)
3		522 (17.5)		0 (0.0)		0 (0.0)
Hemoglobin (g/dL)	2296	14.1 [13.0; 15.2]	872	14.0 [13.2; 15.1]	146	14.0 [13.4; 14.8]
White blood cells (cells/uL)	2294	6390 [5130; 7800]	871	6000 [5130; 7100]	145	6180 [5300; 7130]
Neutrophils (cells/uL)	2284	3700 [2800; 4750]	870	3480 [2890; 4320]	145	3770 [2920; 4570]
Platelets (10/mm3)	2292	249 [210; 292]	869	250 [215; 284]	146	247 [219; 280]
Creatinine (umol/L)	2276	72.0 [62.0; 87.0]	867	70.0 [61.0; 80.0]	144	71.0 [64.0; 81.5]
Alanine aminotransferase (IU/L)	730	25.0 [18.0; 37.0]	0	-	0	-
Aspartate aminotransferase (IU/L)	729	22.0 [18.0; 28.5]	0	-	0	-
Protein-C reactive (mg/L)	2070	3.0 [1.1; 4.6]	787	1.2 [1.0; 4.0]	100	3.8 [1.0; 4.0]
Proteine-C reactive ≥ 5 mg/L	2070	416 (19.6)	787	37 (4.7)	100	9 (9.0)
Lymphocytes < 1000 G/L	2284	225 (9.6)	870	44 (5.1)	145	7 (4.8)

Legend: All characteristics have been collected at the time of inclusion into the cohort.

1-month humoral response following two doses of Covid-19 mRNA vaccines

Percentage of responders

In the control group, 100% (95%CI: 99.6; 100.0) of those aged 18-64 and 99.3% (95%CI: 96.3; 100.0) of those over 65 years developed anti-Spike IgG antibodies.

PLWHIV, diabetic, cancer and obese patients had high rates of responders with 98.7% (95%CI: 97.7; 99.3), 94.2% (95%CI: 91.6; 96.2), 94.2% (95%CI: 89.8; 97.0) and 93.3% (95%CI: 91.4; 94.9), respectively. The lowest percentage of responders was found in SOT (35.9% [95%CI:29.2; 43.0]), HSCT (57.4% [48.1; 66.3]), SEP/NMOSD (68.5% [63.8; 73.0]) and hypogammaglobulinemic populations 77.1% [65.6; 86.3]) (Figure 1 and Supplementary table 12). Patients with chronic renal failure, systemic autoimmune diseases, inflammatory rheumatic diseases, MS/NMOSD had intermediate responses, although lower than control populations. Compare to the control participants, the response was significantly lower in each population (p < 0.01 in each population). After adjustment on age and sex, the difference was still significant (p < 0.01 in each population except HIV participants, p = 0.01).

Figure 1

Percentage of responders with anti-Spike antibodies at one month after the second dose of anti-SARS CoV-2 mRNA vaccine in the different subpopulations and controls of the ANRS0001 S COV-POPART cohort. Legend: SOT: solid organs transplanted, HCT: hematopoietic stem cell transplant, SAD: systemic autoimmune diseases, IRD: inflammatory rheumatic diseases, MS or NMOSD: multiple sclerosis/neuromyelitis optica spectrum disorders, HIV: Human immunodeficiency virus.

Vertical bars indicate 95% confidence interval

Strength of the anti-Spike IgG antibodies response

In the control group, 0.6% (95%CI: 0.2; 1.4) of those aged 18-64 and 4.7% (95%CI: 1.9; 9.4) of those over 65 years were categorized as weak responders. The percentage of weak responders was higher in all subpopulations than in controls with highest rates found in SOT 40.9% (95%CI: 29.3-53.2) and HSCT 30.0% (95%CI: 19.6-42.1). The percentage of strong responders was the highest in controls < 65 years (59.9%, 95%CI: 56.7-63.0) and the lowest in SOT (29.6%, 95%CI: 19.3-41.6) and hypogammaglobulinemic (33.3%, 95%CI: 21.1-47.5). Interestingly some subpopulation had higher percentages of strong responders than controls over 65 years. (Figure 2 , Supplementary Table 13).

Figure 2

Distribution of responders according to the strength of anti-Spike antibodies response at one month after the second dose of anti-SARS CoV-2 vaccine in the different subpopulations and controls of the ANRS0001 S COV-POPART cohort. Legend: SOT: solid organs transplanted, HCT: hematopoietic stem cell transplant, SAD: systemic autoimmune diseases, IRD: inflammatory rheumatic diseases, MS or NMOSD: multiple sclerosis/neuromyelitis optica spectrum disorders, HIV: Human immunodeficiency virus.

anti-SARS-CoV-2-specific neutralizing antibodies

In the control group, 99.8% (95%CI: 99.3; 100.0) of those aged 18-64 and 99.3% (95%CI: 96.3; 100.0) of those over 65 years had specific neutralizing antibodies against SARS CoV-2 D614 strain. PLWHIV, diabetic and obese non-diabetic patients had the highest rates of patient with neutralizing antibodies, 97.3% (95%CI: 95.9; 98.2); 91.0% (95%CI: 87.9; 93.5) and 90.5% (95%CI: 88.2; 92.4) respectively. The lowest percentages of responders were in SOT 32.3% (95%CI: 25.9; 39.3), HSCT 50.8% (95%CI: 41.6-60.0) and hypogammaglobulinemic 72.9% (95%CI: 60.9-82.8) (Figure 3 , Supplementary table 14). Again, patients with chronic renal failure, systemic autoimmune diseases, inflammatory rheumatic diseases, MS/NMOSD had intermediate responses, although lower than control populations. The response in each population was significantly lower compare to the control participants before and after adjustment on age and sex (both p < 0.01 in each population).

Figure 3

Percentage of responders with neutralizing antibodies at one month after the second dose of anti-SARS CoV-2 vaccine in the different subpopulations and controls of the ANRS0001 S COV-POPART cohort. Legend: SOT: solid organs transplanted, HCT: hematopoietic stem cell transplant, SAD: systemic autoimmune diseases, IRD: inflammatory rheumatic diseases, MS or NMOSD: multiple sclerosis/neuromyelitis optica spectrum disorders, HIV: Human immunodeficiency virus.

1-month humoral response following three doses of Covid-19 mRNA vaccines

The third dose added as primary vaccination increased the rate of responders in those who received a third dose in all concerned subpopulations reaching 54.2% (45/83) (95%CI: 42.9-65.2) (vs. 36.5 (95%CI: 29.2-44.3) after dose 2) in SOT and 73.9% (34/46) (95%CI: 58.8-85.7) (vs. 56.1% (95%CI: 46.2-65.7) after dose 2) in HSCT (Figure 4 and supplementary table 15). Of note, geometric mean titers of anti-Spike SARS-CoV-2 IgG antibodies after three doses reached similar levels than those after two doses in those who received only 2 doses except in MS/NMOSD and hypogammaglobulinemic patients (Supplementary Figure 2 and supplementary table 16).

Figure 4

Percentage of responders with anti-Spike antibodies at one month after the second and one month after the third dose of anti-SARS CoV-2 vaccine in participants from the ANRS0001S COV-POPART cohort who received three doses as a primary vaccination. Legend: SOT: solid organs transplanted, HCT: hematopoietic stem cell transplant, SAD: systemic autoimmune diseases, IRD: inflammatory rheumatic diseases, MS or NMOSD: multiple sclerosis/neuromyelitis optica spectrum disorders, HIV: Human immunodeficiency virus.

The rate of patients with neutralizing antibodies increased in all subpopulations reaching 47.0% (95%CI: 35.9-58.3) (vs. 32.9% (95%CI: 25.9-40.6) after dose 2, p=0.01) in SOT, 69.8% (95%CI: 53.9-82.8) (vs. 48.6% (95%CI: 38.8-58.5) after dose 2, p=0.05) in HSCT. The increase was only moderate in MS/NMOSD (30.4% (95%CI: 20.5-41.8) vs. 16.7% (95%CI: 10.3-24.8) after dose 2) and inflammatory rheumatic diseases patients (40.0% (95%CI: 12.2-73.8) vs. 23.8% (95%CI: 8.2-47.2) after dose 2) (Supplementary Figure 3 and supplementary table 17). Geometric mean titers of neutralizing antibodies reached similar levels than the ones one month after dose 2 in those who received only 2 doses (Supplementary Figure 4 and supplementary table 18).

Anti-CD20 treatments among the immunosuppressive treatment regimen in MS/NMOSD and autoimmune inflammatory rheumatic diseases patients was frequent (32.0% and 11.0% in the study, respectively). The rate of responders in MS/NMOSD receiving anti-CD20 who received a third dose reaches 40.9% (95%CI: 29.0-53.7) (vs. 16.7% (95%CI: 9.6-26.0) after dose 2) compared to 72.2% (95%CI: 46.5-90.3) (vs. 41.7% (95%CI: 22.1-63.4) after dose 2) in MS/NMOSD not receiving anti-CD20 who received a third dose.

Overall humoral response one month after the end of primary Covid-19 mRNA vaccines regimen (two doses or three doses)

When pooling humoral responses 1 month after the second dose on those who received only two doses and 1 month after the third dose in those who received three doses, we observed that control groups and all specific populations groups but SOT, HSCT, CKD, MS/NMOSD and Hypogammaglobulinemic had 90% and more responders in both anti-Spike SARS-CoV-2 IgG and neutralizing antibodies. The lowest rate of responders was in SOT with 48.3% (95%CI: 38.8-57.8) and 42.1% (95%CI: 32.9-51.7) for anti-Spike SARS-CoV-2 IgG and neutralizing antibodies respectively (Supplementary table 19). Among seroresponders, the overall proportion of strong responders was 50.5% (95%CI: 48.8-52.1), 47.3% (95%CI: 45.3 – 49.3) in specific populations and 59.9% (95%CI 56.7-63.0) in controls < 65 years. Autoimmune inflammatory rheumatic diseases patients had the lowest percentage of high responders followed by SOT despite a high proportion of patients who received three doses as primary vaccination regimen in the latter and hypogammaglobulinemic (Supplementary table 20).

Discussion

The ANRS0001S COV-POPART is, to the best of our knowledge, the largest cohort assessing response to Covid-19 vaccines in specific populations to date.

These first results showed first, that the humoral response in these populations 1 month after receiving two doses of mRNA covid-19 vaccines was heterogeneous compared to controls. This response was noticeably low in patients with SOT, HSCT, hypogammaglobulinemia and MS/NMOSD. On the contrary, PLWHIV, obese patients and those with cancer or diabetes had good response rates. Second, that the strength of humoral neutralizing response was lower in all subgroups investigated here compared to control groups.

Third, that a third dose of vaccine in the primary regimen had a positive effect on the humoral response at 1 month after the third dose on both percentages of patients who developed anti-Spike IgG antibodies and specific neutralizing antibodies. However, this effect was only moderate in some subgroups such as participants with MS/NMOSD hypogammaglobulinemia and inflammatory rheumatic diseases, as a lower increase in anti-Spike IgG antibodies geometric mean titers and specific neutralizing antibodies geometric mean titers was observed when compared to patients who received only two doses.

These results are in line with the existing literature showing an overall blunted humoral responses in immunocompromised populations [1,2] that can be increased by a third [7] or a fourth [11,12] Covid-19 mRNA vaccine additional dose. We highlighted the negative impact of Anti-CD20 treatments in the response to additional dose in MS/NMOSD and inflammatory rheumatic diseases patients as previously showed in the literature in patients receiving two doses [13,14] of more [15]. This could also contribute to the increased risk of severe Covid-19 in MS patients treated with anti-CD20 [16].

Although there is no clear correlate of protection, especially in the context of Omicron variants circulation, it is important to induce high antibodies titers and cellular response in these populations at-high risk of severe Covid-19. Anti-Spike IgG antibodies monitoring following vaccination is thus important to allow the indication of a third dose of vaccine and the use of SARS-CoV-2 mAbs as pre-exposure prophylaxis. The assessment of heterologous vaccine scheme especially with adjuvanted recombinant protein vaccines would be of interest as well as the evaluation of the persistence of the humoral response.

Our study has some limitations including the inherent bias of a cohort (i.e descriptive data, possible lack of representativeness of the included participants in each sub-population), the limited sample size for statistics in some populations, the lack of cellular response data and the lack of data of neutralizing antibodies against Omicron variant of concern.

Strengths of this study include its large sample with several different specific populations and two control groups with geographical representativity of the country, the standardized timeline of assessment, and the standardized centralized analyses of the results.

In conclusion these first results show that specific populations had a lower humoral response one month after receiving two doses of Covid-19 mRNA vaccines than in general population. This response was heterogeneous between subpopulations. Our results highlight the importance of humoral response assessment at the end of a 2-dose mRNA vaccine regimen in these populations. The additional third dose allowed increasing this response in non/low responders to two doses but to levels still lower than those observed in controls.

Conflict of interest

PL has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astrazeneca, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi Pasteur and Support for attending meetings and/or travel from Pfizer, Sanofi Pasteur.

JM has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Biogen, BMS, Boerhinger Ingelheim, Galapagos, GSK, Fresenius Kabi, Lilly, Mylan, Novartis, Pfizer, Sanofi and grants outside the submitted work from Lilly, Novartis.

JPS has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer and Astrazeneca.

OL has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi Pasteur; Pfizer, Janssen and, non-financial support from Sanofi Pasteur; Pfizer, Janssen, GlaxoSmithKline and grant from GlaxoSmithKline.

The other authors declare having no conflict of interest.

Funding

Funding was received from ANRS│MIE and the French ministries (Ministère des Solidarités et de la Santé and Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation)

Contribution

Original Draft: P.L, and L.W.; Writing – Review & Editing: L.N., B.B., JY.B., M.H., E.T., M.L, B.L., JD.L., J.M., S. NQ., JP.S., B.T., A.T., JF.V., F.V., S.C., P.V., E.T., B.P., X.L.,; Conceptualization: P.L, L.W and O.L.; Investigation: P.L, L.N., B.B., JY.B., M.H., E.T., M.L, B.L., JD.L., J.M., S. NQ., JP.S., B.T., A.T., JF.V., F.V., S.C., P.V., E.T., B.P., X.L.,; Methodology: L.W and M.C; Formal Analysis: L.W. and M.C; Project Administration: P.L., L.W., L.E., A.L., E.T., X.L. and O.L.

Uncited References

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