To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people.Systematic review and meta-analysis.PubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies.Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants.A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed.82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I2=80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I2=89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I2=89%; 0.29, 0.11 to 0.58, I2=97%), and solid cancers (0.55, 0.46 to 0.65, I2=78%; 0.44, 0.36 to 0.53, I2=84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I2=0%; 0.06, 0.04 to 0.08, I2=0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I2=92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I2=88%; 0.62, 0.54 to 0.70, I2=90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I2=92%; 0.77, 0.66 to 0.85, I2=93%), and solid cancers (0.90, 0.88 to 0.93, I2=51%; 0.89, 0.86 to 0.91, I2=49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I2=0%; 0.97, 0.83 to 1.00, I2=89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines.Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed.PROSPERO CRD42021272088. 

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Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis

Patients with cancer have a higher risk of severe coronavirus disease (COVID-19) and associated mortality than the general population. Owing to this increased risk, patients with cancer have been prioritized for COVID-19 vaccination globally, for both primary and booster vaccinations. However, given that these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, and the extent of humoral and cellular immune responses in these patients, as well as the risks of vaccine-related adverse events. In this Review, we summarize the current knowledge generated in studies conducted since COVID-19 vaccines first became available. We also highlight critical points that might affect vaccine efficacy in patients with cancer in the future. 

/pdf/covid-19-vaccines-in-patients-with-cancer-immunogenicity-3po2jasy.pdf

COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety

Host genetic and environmental factors including age, biological sex, diet, geographical location, microbiome composition and metabolites converge to influence innate and adaptive immune responses to vaccines. Failure to understand and account for these factors when investigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy may impair the development of the next generation of vaccines. Most studies aimed at identifying mechanisms of vaccine-mediated immune protection have focused on adaptive immune responses. It is well established, however, that mobilization of the innate immune response is essential to the development of effective cellular and humoral immunity. A comprehensive understanding of the innate immune response and environmental factors that contribute to the development of broad and durable cellular and humoral immune responses to SARS-CoV-2 and other vaccines requires a holistic and unbiased approach. Along with optimization of the immunogen and vectors, the development of adjuvants based on our evolving understanding of how the innate immune system shapes vaccine responses will be essential. Defining the innate immune mechanisms underlying the establishment of long-lived plasma cells and memory T cells could lead to a universal vaccine for coronaviruses, a key biomedical priority. In part of a series of commissioned pieces on coronavirus disease 2019 (COVID-19), Sekaly and colleagues discuss COVID-19 vaccine progress, the underlying biology and prospects for the future. 

/pdf/fighting-the-sars-cov-2-pandemic-requires-a-global-approach-3hv3bf0b.pdf

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses

Vaccination programs against SARS-CoV-2 constitute the mainstay of public health interventions against the global COVID-19 pandemic. Currently available vaccines have shown 90% or better rates of protection against severe disease and mortality. Barely a year after vaccines became available, the Omicron variant and its unprecedented speed of transmission has posed a new challenge. Overall, Omicron presents increased immune escape, transmissibility, and decreased pathogenicity. Vaccines do not offer a full protection against SARS-CoV-2 acquisition, since "breakthrough" infections may occur in fully vaccinated individuals, who may in turn spread the virus to others. Breakthrough infections may be causally related to the viral profile (viral variant and load, incubation period, transmissibility, pathogenicity, immune evasion), immunity characteristics (mucosal versus systemic immunity, duration of immunity, etc.), host determinants (age, comorbidities, immune status, immunosuppressive drugs) and vaccination properties (platform, antigen dose, dose number, dose interval, route of administration). Determining the rate of breakthrough infections may be challenging and necessitates the conduction of population-based studies regarding vaccine effectiveness as well as neutralizing antibody testing, a surrogate of immune protection. In this review, we analyze the causes of breakthrough infections, their clinical consequences (severity of infection and transmission), methods of determining their incidence as well as challenges and perspectives. Long COVID as well as multi-inflammatory syndrome in adolescents may be significantly reduced in breakthrough infections. The need for universal pancoranavirus vaccines that would aim at protecting against a plethora of SARS-CoV-2 variants as well as emerging variants is discussed. Finally, novel vaccine strategies, such as nasal vaccines, may confer robust mucosal and systemic protection, reducing efficiently transmission. 

Breakthrough infections after COVID-19 vaccination: Insights, perspectives and challenges

Patients with cancer are at increased risk for severe COVID-19 and have reduced humoral immune responses after SARS-CoV-2 infection and dual-dose BNT162b2 vaccination [1,2]. Recently, it was observed that the third dose of BNT162b2 is able to elicit higher SARS-CoV-2 anti-receptor-binding domain (RBD) IgG titres in solid-organ transplant patients and adults aged ≥60 years than two doses [3,4]. Initial reports with limited sample size also indicated that the third BNT162b2 vaccination dose would be beneficial for patients with solid tumour receiving active anti-neoplastic treatment [5–7]. 

Antibody titres before and after a third dose of the SARS-CoV-2 BNT162b2 vaccine in patients with cancer

BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

Background: Cancer patients are at higher risk of developing severe COVID-19. However, safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment is unclear.

Methods: In this interventional prospective multi-cohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted- or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Primary endpoint was anti-SARS-CoV-2 receptor binding domain (RBD) antibody level at 28 days post-booster. Anti-RBD IgG titers above 200 IU/ml was used to define high-responders as it leads to a neutralization response required for 50% protection against symptomatic SARS-CoV-2 infection in 268 independent subjects. Secondary endpoints included self-reported adverse events (AEs), antibody response over time and number of breakthrough infections after vaccination.

Findings: 28 days post-booster vaccination of 197 cancer patients, antibody response was lower in the hematological cohort (geometric mean titer (GMT) 17·61 IU/mL [95% CI 7·17-43·24]) and the chemotherapy cohort (GMT 234·05 IU/mL [95% 95%CI 122·10-448·66]) when compared to healthy individuals (n=40; GMT 1844·93 IU/mL [95% CI 1383·57-2460·14]), irrespective of timing of vaccination during chemotherapy cycles. Only 55% and 7% of patients receiving chemotherapy or rituximab could be categorized as high-responders at 28 days post-booster. During the study period, five subjects tested positive for SARS-CoV-2 infection, including three after full vaccination. Local and systemic AEs were mostly mild to moderate, with only 1-3% of patients experiencing severe AEs. 

Local, but not systemic, AEs occurred more frequently after booster than after priming dose.

Interpretation: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

Trial Registration: EudraCT number 2021-000300-38

Funding: The regulatory sponsor was the Antwerp University Hospital (EudraCT number 2021-000300-38). The trial was funded by the Belgian Government through Sciensano (COVID-19_SC004, COVID- 19_SC059, COVID-19_SC061).

Declaration of Interest: MP declares to have an advisory role within Remedus, all other authors declare no competing interests.

Ethical Approval: The study was approved by the local ethics committee and was executed in accordance with Good Clinical Practice and the Declaration of Helsinki (ICH GCP E6(R2)).

Bart Peeters

Papers

Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

Antibody Response after BNT162B2 COVID-19 mRNA Vaccination in Cancer Patients Under Anti-Neoplastic Treatment