key: cord-0694445-spuuk5t9
authors: Gounant, Valérie; Ferré, Valentine Marie; Soussi, Ghassen; Charpentier, Charlotte; Flament, Héloïse; Fidouh, Nadhira; Collin, Gilles; Namour, Céline; Assoun, Sandra; Bizot, Alexandra; Brouk, Zohra; Vicaut, Eric; Teixeira, Luis; Descamps, Diane; Zalcman, Gérard
title: Efficacy of SARS-CoV-2 vaccine in thoracic cancer patients: a prospective study supporting a third dose in patients with minimal serologic response after two vaccine doses
date: 2021-11-16
journal: J Thorac Oncol
DOI: 10.1016/j.jtho.2021.10.015
sha: 53d40edb43ed91c921644aa6c65af004ac281073
doc_id: 694445
cord_uid: spuuk5t9

Hypothesis Coronavirus disease 2019 (COVID-19) resulted in a 30% mortality rate in thoracic cancer patients. Given that cancer patients were excluded from serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine registration trials, it is still unknown whether they would develop a protective anti-spike antibody response following vaccination. This prospective vaccine monitoring study primarily aimed to assess humoral responses to SARS-CoV2 vaccine in thoracic cancer patients. Methods SARS-CoV2-spike antibodies were measured using Abbot ARCHITECT SARS-CoV-2 IgG immunoassay, prior to first injection of BNT162b2 mRNA vaccine, as well as at Week 4, and two-to-sixteen weeks after second vaccine dose. The factors associated with antibody response were analyzed. Results Overall, 306 patients, with a median age of 67.0 years (IQR=58-74), were vaccinated. Of these, 283 patients received two vaccine doses at 28-day intervals. After 6.7-month median follow-up, eight patients (2.6%) contracted proven symptomatic SARS-CoV-2 infection, with rapid favorable evolution. Of 269 serological results available beyond Day 14 post-second vaccine dose, 17 (6.3%) were still negative (<50 AU/mL) (arbitrary units/mL), while 34 (11%) were <300 AU/mL (12.5th percentile). In multivariate analysis, only age and chronic corticosteroid treatment were significantly associated with a lack of immunization. Thirty patients received a third vaccine dose, with only three patients showing persistent negative serology thereafter, whereas the others demonstrated clear seroconversion. Conclusion SARS-CoV2 vaccines were shown to be efficient in thoracic cancer patients, most of them being immunized after two doses. A third shot given to 1% of patients with persistent low antibody titers resulted in a 88% immunization rate.

Coronavirus disease 2019 is associated with a dramatic 30% mortality rate in thoracic cancer patients 1, 2, 3 . The Chinese series reported mortality rates of 29-39%, 4-6 compared with 0.7-8.0% case fatality rates in their general population [7] [8] [9] [10] [11] .

Lung cancer patients should therefore be given priority for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Nonetheless, active cancer condition and immunosuppressive therapy constituted non-inclusion criteria for SARS-CoV-2 vaccine registration trials, and scarcely anything is known about the vaccine effectiveness in cancer populations. Moreover, the antibody response after influenza vaccination was previously shown to be lower in cancer patients versus healthy controls, especially concerning people aged >65 years 12 . Notably, two doses of influenza vaccine were required in cancer patients to attain the same serum protection rate than in healthy controls, with on-going chemotherapy or corticosteroids resulting in lower protection 13 . Similarly, a meta-analysis on influenza vaccine effectiveness in cancer patients exhibited significantly reduced seroconversion (>four-fold rise) in comparison with vaccinated immunocompetent controls (0.31; 95%CI:0.22-0.43) 14 . Vaccination timing remains unclear too. Upon chemotherapy, the mid-point between two cycles was empirically selected for the vaccine shot. Moreover, as immunotherapy has become an essential component of lung cancer treatment, only little is known concerning undesirable effects, although no short-term reactogenicity following influenza vaccination occurred in patients under immune checkpoints inhibitors (ICIs) 15 were confirmed in real-life by population-based Israeli and Scottish studies for Pfizer BNT162b2 or ChAdOx1nCov-19 22, 23 . Yet, these data cannot be extrapolated to cancer patients undergoing anti-cancer treatment. Duration of anti-SARS-CoV-2spike (anti-S) detection was at least 8 months in healthy volunteers 24 . It is unclear whether such duration is applicable to cancer patients receiving immunosuppressing drugs. Early January 2021, vaccination was made available in France. To increase first vaccine dose availability, French Health authorities recommended a 28-day interval for both mRNA vaccines, with a 42-day interval for healthy people, this delayed second dosing being debatable 25, 26 . Due to uncertainties concerning vaccination of cancer patients, the observational COVIDVAC-OH study (clinical.trials.gov NCT04776005) was launched, sponsored by Paris University

Hospitals. This study sought to investigate SARS-CoV-2 vaccination's (mainly mRNA-based vaccines) effectiveness in over 1100 consecutive patients with solid cancers or hematological malignancies, at North-Paris University Cancer center. This report concerns 306 thoracic cancer patients.

We conducted a prospective study involving thoracic cancer patients followed-up in Bichat Hospital, from January 26 to July 28, 2021. Patients diagnosed with thoracic cancer and deemed eligible (no known COVID-19 infection within <last three months; life expectancy >3 months; lack of known allergy to previous vaccines) were J o u r n a l P r e -p r o o f 6 identified from medical records. They were contacted and offered to be vaccinated. If they accepted and in the absence of contra-indications, they were attended vaccination sessions in the outpatient clinic, according to priority sequencing, as follows: first elderly patients aged >75 years and those receiving chemotherapy; patients receiving immune checkpoint inhibitors (ICI); patients with pneumonectomy or chronic radiation pneumonitis; patients on oral tyrosine kinase targeted therapy (TKIs); patients without systemic therapy. They were given a written information leaflet on COVID19 mRNA BNT162b2 vaccine, and on serological and hematological blood tests to be performed at first dose (Day 0), at second dose (Day 28), and at least 2 weeks post-booster dose (Day 42). All patients could oppose blood samplings and still undergo vaccine injections. Recommendations to keep facial masks and social distancing were given. All patients were registered into National Health

Insurance computed COVID-19 vaccine database, with national identification number, complete identity, main underlying conditions, and vaccine batch number.

Following blood sampling and vaccine injection, patients were followed-up for 15 minutes under medical surveillance 27 . This study was approved by Paris-North institutional review board (IRB) (IRB 00006477, approval N°CER-2021-72). In the case of COVID-19-suggestive symptoms, patients were instructed to promptly inform the medical team and perform nasopharyngeal SARS-CoV-2 RT-PCR swab testing.

At second vaccination visit, they were questioned about undesirable events post-first vaccination and symptoms evoking COVID-19. Some patients (n=16) were vaccinated by their general practitioner or in a government-certified vaccination center. No blood sampling was available for these patients at Days 0 and 28. If they agreed, they underwent blood sampling in the post-booster period and were included in our study. 

The primary endpoint was to assess humoral immunity against SARS-CoV-2-spike in thoracic cancer patients following COVID-19 mRNA BNT162b2 vaccine injection and booster dose. Some patients vaccinated outside our center received Moderna mRNA-1273 (n=1) or Astra-Zeneca ChAdOx1 nCov-19 (n=3) vaccines, being included herein.

Secondary endpoints were vaccination safety, clinical efficacy based on RT-PCRdocumented COVID-19 infection during the study, and hospitalization or death from COVID-19. Phone safety consultations were scheduled every 3 weeks. Cell immunity to SARS-CoV-2-spike protein was evaluated using T-cell enzyme linked immunospot (ELISPOT), with lymphocyte subset counts, scheduled at Day 28 and from Day 42 post-first injection in 122 arbitrarily-designated patients.

SARS-CoV-2 anti-N and anti-S antibody titers were determined using Abbott Architect SARS-CoV-2 IgG and IgG Quant II (Abbott, Maidenhead, UK) and expressed as index (cut-off: 0.49) and arbitrary units (cut-off: 50 AU/mL), respectively. Pseudo-neutralization assay was performed using iFlash-2019-nCoV J o u r n a l P r e -p r o o f 8 Nab assay (YHLO, Shenzhen, China), which assesses antibody neutralizing capacity by competition with angiotensin-converting enzyme 2 (ACE2)-receptor for binding to anti-spike RBD (cut-off: 10 AU/mL). This assay correlated with SARS-CoV-2 in vitro cell micro-neutralization. This pseudo-neutralization assay was validated against invitro micro-neutralization of SARS-CoV-2 B. strain. To this end, serial sera samples from nine healthy controls were decomplemented by heat inactivation, subjected to serial two-fold dilution (1:25 to 1:12800), and incubated with virus (2 × 10 3 Plaque Forming Units [PFU]/ml) for 60 min; Vero E6 cell suspension was then added, and a 4-day incubation carried out until the microscopy examination was conducted on Day 4 to assess the cyto-pathological effects (paper submitted for publication).

Overall, 122 and 74 patients who accepted larger blood sampling and received their vaccine injection in the morning (in order to enable peripheral blood mononuclear cells isolation procedure to be performed within the day) underwent CD3+ and CD4+ T-cell quantification at Day 28 (before the second shot) and Day 42 or beyond, respectively. At Day 28, 115 patients out of 122 underwent successful determination of T-cell responses to SARS-CoV-2 vaccination, as assessed using IFN-γ ELISpot assay and described in online supplemental material.

All samples were de-identified and assigned an ID number, with the sampling date.

Sample processing and data analyses were performed, with all study personal blinded to information concerning patients and samples. De-identified data were exported from Microsoft Excel Version 2013 for Windows (Microsoft Corporation, 9 2013 ) to IBM® SPSS® Statistics for Windows, Version 25.0 (IBM Corp., Armonk, N.Y., USA) for statistical analysis.

Normality for each continuous variable was systematically checked in each subgroup (immunized/non-immunized) by means of analyzing skewness and kurtosis, QQ plots, and Shapiro-Wilk's testing, as well. When the normality assumption was not verified in both subgroups, non-parametric tests were applied.

Pairwise between-group comparisons were performed using Pearson's chi-squared or Fisher's exact tests for discrete variables, and Student's-T or Mann-Whitney U tests for continuous variables. Odds ratios (OR) and respective 95% confidence intervals (95%CI) were calculated using binary logistic regression. Hypothesis testing was two-tailed, with p values<0.05 considered statistically significant. In multivariable analysis, only variables exhibiting a p-value <0.2 in univariable analyses were considered, except for T-cell counts and SARS-CoV-2 specific T-cells because of their small sample size. The assumptions of the logistic regression were thoroughly checked, as follows: multicollinearity using Spearman's rho bivariate correlation testing, outliers' identification using the Z-score method, and log odds linearity using the Box-Tidwell method. Multivariable analysis was conducted using binary logistic regression using the Enter method, including variables exhibiting a significance threshold p<0.20 yielded by the univariable analysis. The 50 AU/mL cutoff threshold for positivity of the Abbott assay was provided by the manufacturer. The 300 AU/mL value was data-driven, corresponding to 12.5 th distribution percentile of anti-S IgG titers after the first vaccine injection. This precise value has been recently reported to significantly discriminate high versus low risk of breakthrough SARS-CoV-2 infection in fully vaccinated people at 6 months post vaccination 28 . J o u r n a l P r e -p r o o f

The academic authors retained editorial control. The Assistance Publique-Hôpitaux de Paris funded the study, without participating to study design, data collection, data analysis, data interpretation, or report writing.

From January 20 to June 1, 2021, overall 325 thoracic cancer patients followed-up in thoracic oncology/surgery departments were proposed anti-SARS-CoV-2 vaccination with Pfizer BNT162b2 mRNA vaccine. Initially, only 36 (11%) declined the proposal.

Of these, 17 eventually accepted to be vaccinated; nine of whom were vaccinated outside of our center but participated to serological testing. Among them, three 

In patients without a history of symptomatic or asymptomatic COVID-19 (thus excluding twenty-two patients, 17 with prior COVID-19 history, three with PCRproved COVID-19 post-1st dose, and two with anti-N IgG detected at Day 0) history, a striking increase in antibody titers occurred between Day 0 (137 patients with available serology) and Day 28 (248 patients with available serology) post-first vaccine ( Figure 1A) . Not all antibodies detected are able to efficiently neutralize the virus by impairing its binding to the ACE2 receptor expressed by respiratory cells. Neutralizing antibodies constitute a variable part of the anti-spike antibodies. The neutralization activity was measured using a pseudo-neutralization assay, assessing neutralizing antibody capacity via competition with ACE2-receptor for binding to anti-spike RBD. Suppl. Only one patient with thymic carcinoma (serum anti-S IgG titers at 300.4 AU/mL two days before positive SARS-CoV-2 PCR testing) was hospitalized, due to his frail condition, yet without requiring oxygen supply. He was discharged a week later.

No anaphylaxis reaction occurred among the 306 patients, with 587 vaccine doses administered. Safety data were available for 278 patients (90.1%), without significant safety concerns. One-third of patients (n=98) did not report symptoms post-first injection. Reported undesirable effects were transitory pain, injection-site swelling, or 

We analyzed the correlation between serological titers using different cut-points (<50 AU/mL; <300 AU/mL) and the main clinical, demographic, and biological variables in the whole population with two mRNA vaccine injections (n=283) (suppl. Table 1A Briefly, at Day 28, either with the 50 AU/mL or the 300 AU/mL cut-off, age (suppl. immunotherapy as single-therapy within the last three months, or long-term corticosteroids were significantly associated with negative (< 50 AU/mL) or low (< 300 AU/mL) serum anti-S IgG levels in univariable analyses (suppl . Table 2A) .

Conversely, in 122 patients with such analyses, at 50 AU/mL cut-off, each 100 units/mm3 increase in Day 28 T-lymphocyte (CD3+) counts (p <0.01), and Day 28 CD4+ T-cell counts (p=0.01, suppl. Fig. 4B ), were associated with higher seroconversion probability while this was not the case for both T-cell subsets, with the 300 AU/mL cutoff. In 111 and 108 patients with these analyses, Day 28 interferon-γ specific T-cell response to SARS-CO-2-spike, measured by ELISPOT assay, was significantly associated with higher seroconversion probability at Day Chemotherapy as last treatment received was not retained in the model for the 50 AU/mL cut-point. However, at 300 AU/mL cut-off, chemotherapy as last treatment received (aOR 2.55; 95%CI: 0.90-7.28; p=0.08), although close to significance, failed to predict a lower probability of seroconversion in patients without COVID-19 history, whereas it did predict such lack of seroconversion in the whole series of patients (supl . Table 1D ), with aOR 3.14, 95%CI: 1.08-9.13;p=0.03).

Serial serological tests were performed in ten patients exhibiting low antibody previous reports, with only 11% initial refusals 30 . Reactogenicity was weak, without short-term serious adverse effects in this real-life setting. We did not observe specific safety concerns in ICI-treated patients, especially regarding immune-related sideeffects, as reported by Israeli teams 31 . Moreover, our study emphasized that seroconversion monitoring could be useful in immuno-suppressed patients. In this population, the first vaccine efficacy was much lower than that reported in vaccine registration trials, with one-third of patients displaying negative serological testing (≤50 AU/mL) at Day 28, whereas three-quarters exhibited <25 th percentile serological titer distribution. These data are in line with prospective studies involving a mixed population with solid cancers and hematological malignancies 32, 33 . Although there has been no clear cut-off for antibody titers predicting protection against severe COVID-19, a 300 AU/mL cut-off was shown here to well correlate with the pseudoneutralization assay, as a readout for anti-viral efficacy. Similarly, a recent Israeli study reported, based on 5,141 vaccine recipients, that such value was able to discriminate between a 2.3% risk of breakthrough SARS-CoV-2 infection (for people with lower titers) and low risk of 0.2% (for vaccinated people with higher titers), six months after the vaccine injections 28 . We thus selected this value as protection cutoff against SARS-CoV-2 infection in our patients 34 . Let us keep in mind that the recently described delta strain one of the variant strains of concern (VOC), which currently represents more than 90% of sequenced viral isolates in France 35 , was reported to be 40-80% more transmissible than the alpha strain 36, 37 , its viral burden being 1000 fold higher than other strains 38 . It is thus crucial to define serological correlates confirming the protection of immuno-compromised patients. Although a J o u r n a l P r e -p r o o f 20 strong relationship between mean neutralization levels and reported protection was evidenced in a recent meta-analysis 34 , neutralizing antibodies (Nabs) are not the only described correlates for protection against viral infection, since specific anti-SARS-CoV-2 memory T-and B-cells have also been reported to play an important role 39 . However, several authors described waning specific T-cell immunity (specifically against the delta VOC) in parallel to humoral immunity waning over time, which especially occurred in elderly people 40 .

With this in mind, our study provided strong evidence for keeping the initially established intervals between two vaccine shots for cancer patients. These patients displayed a delay in their immunization process, with lower levels of protective circulating vaccination-induced antibodies versus healthy vaccinated controls.

Conversely, a reassuring observation has been the booster injection's remarkable efficacy, with only 6.0% of thoracic cancer patients still displaying negative serology at Day 42, whereas only % exhibited antibody titers ≤300 AU/mL. The two characteristics independently associated with poor immunization, irrespective the cutpoint chosen, were age and long-term corticosteroids. Concerning age, a lower immunization rate was identified in octogenarians, along with a 5% decreased probability per year to reach protective immunization. Regarding long-term corticosteroids, the lower immunization may probably be explained by either lower total T-cell and CD4+ T-lymphocyte counts or T-cell specific responses to spike protein. The adverse impact of age on the ability to induce vaccine-related protective humoral responses was already highlighted in studies involving octogenarians [40] [41] [42] .

While clearly delaying the immunization process as previously reported 32, 43, 44 , cytotoxic chemotherapy was also associated with higher low-immunization rates at Day 42, as well. 3) Because of the observational study design, we did not perform systematic recurrent rhino-pharyngeal swabs for SARS-CoV-2 molecular diagnosis. Therefore, we possibly did not capture the asymptomatic infection events. Nevertheless, we did not observe anti-N sero-conversion events during the follow-up period until September 2021. Based on this, we believe that we did not miss a large body of such asymptomatic infection events.

As herein shown, a third vaccine could contribute to appropriate sero-protection in Supp. Figure 4A , B & C:

Suppl. Figure Suppl. Figure 4B : Distribution of patients' T-lymphocyte counts according to Day 28 anti-S IgG antibody titers, above or below 50 AU/mL. Statistical comparison used

Mann-Whiney U test.

Suppl. Figure 4C : Distribution of patient ages according to Day 28 anti-S IgG antibody titers, above or below 300 UA/mL. Statistical comparison used Mann-Whiney U test.

Suppl. 

Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation using Lymphosep TM (1.077 g/ml, Biosera, France). 6 ml of whole blood was diluted 1:1 with PBS. 15 ml of Lymphosep was pipetted into 50-ml SepMate TM centrifuge tubes (Stem Cell Technologies), and the diluted blood was layered over the Lymphosep gradient. The tubes were centrifuged for 10 min at 1200 × g with break. After centrifugation, PBMCs were collected and washed twice in PBS. For cryopreservation, PBMCs were diluted with 4°C heat-inactivated fetal calf serum (FCS, Gibco TM , Thermo Fischer Scientific) containing 10% DMSO and stored at −80°C until further use.

The cryopreserved PBMC samples were thawed in a 37°C water bath with gently agitation. Thereafter, the cell suspension was resuspended in 10 ml of pre-warmed RPMI 1640 medium (Gibco TM , Thermo Fischer Scientific) supplemented with 10% heat-inactivated FCS and 100 UI/ml Penicillin/Strepomycin (Gibco TM , Thermo Fischer Scientific). After centrifugation, cells were resuspended in complete RPMI medium and counted using a hematology analyzer XE-5000 (Sysmex, Kobe, Japan).

T cell responses to SARS-CoV-2 vaccination were assessed by IFN-γ ELISpot assay using a T-SPOT.COVID kit (Oxford Immunotec, Abingdon, UK). Thawed PBMCs were resuspended at 2.5x10 6 lymphocytes/ml in AIMV medium (Thermo Fischer Scientific). PBMCs were seeded (100 l per well) and stimulated for 16-18 h with a pool of SARS-CoV-2 spike peptides at 37 °C, 5% CO2, 95% humidity. Subsequently, cells were washed off and released IFN-γ was detected following the manufacturer's instructions. Spot forming units (SFU) were counted manually using a DX-1 Microscope (Veho, UK). Results were reported as SFU per million lymphocytes. The unspecific background (SFU from negative control wells) was subtracted from experimental readings. We excluded the results if the positive control well (phytohemagglutinin) was negative. The lower limit to indicate a positive response was 32 spots per million lymphocytes.

T-(CD3+, CD3+CD4+, CD3+CD8+), B-(CD19+), and Natural Killer (NK)-lymphocyte (CD3negCD16 + CD56+) absolute counts were enumerated by multiparametric flow cytometry of fresh EDTA-anticoagulated whole peripheral blood (PB). PB samples were processed using a BD FACSDuet™ preparation system integrated with a BD FACSLyric™ flow cytometer (Becton Dickinson Biosciences, San Jose, CA). Lymphocyte subpopulations were assessed using BD Multitest™ CD3/CD8/CD45/CD4, BD Multitest™ CD3/CD16+CD56/CD45/CD19 and BD Trucount™ tubes for absolute count with a single step "lyse-no-wash" procedure (BD FACS™Lysing Solution). BD FACS Suite™ Clinical software version 1.4 was used to collect and analyze the data.

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