Safety and immunogenicity of a reduced dose of the BNT162b2 mRNA COVID-19 vaccine (REDU-VAC): A single blind, randomized, non-inferiority trial

Fractional dosing of COVID-19 vaccines could accelerate vaccination rates in low-income countries. Dose-finding studies of the mRNA vaccine BNT162b2 (Pfizer-BioNTech) suggest that a fractional dose induces comparable antibody responses to the full dose in people <55 years. Here, we report the safety and immunogenicity of a fractional dose regimen of the BNT162b2 vaccine. REDU-VAC is a participant-blinded, randomised, phase 4, non-inferiority study. Adults 18–55 years old, either previously infected or infection naïve, were randomly assigned to receive 20μg/20μg (fractional dose) or 30μg/30μg (full dose) of BNT162b2. The primary endpoint was the geometric mean ratio (GMR) of SARS-CoV-2 anti-RBD IgG titres at 28 days post second dose between the reduced and full dose regimens. The reduced dose was considered non-inferior to the full dose if the lower limit of the two-sided 95% CI of the GMR was >0.67. Primary analysis was done on the per-protocol population, including infection naïve participants only. 145 participants were enrolled and randomized, were mostly female (69.5%), of European origin (95%), with a mean age of 40.4 years (SD 7.9). At 28 days post second dose, the geometric mean titre (GMT) of anti-RBD IgG of the reduced dose regimen (1,705 BAU/mL) was not non-inferior to the full dose regimen (2,387 BAU/mL), with a GMR of 0.714 (two-sided 95% CI 0.540–0.944). No serious adverse events occurred. While non-inferiority of the reduced dose regimen was not demonstrated, the anti-RBD IgG titre was only moderately lower than that of the full dose regimen and, importantly, still markedly higher than the reported antibody response to the licensed adenoviral vector vaccines. These data suggest that reduced doses of the BNT162b2 mRNA vaccine may offer additional benefit as compared to the vaccines currently in use in most low and middle-income countries, warranting larger immunogenicity and effectiveness trials. Trial Registration: The trial is registered at ClinicalTrials.gov (NCT04852861).

Third dose of COVID-19 mRNA vaccine closes the gap in immune response between naïve nursing home residents and healthy adults.

BACKGROUND: Nursing home residents, a frail and old population group, respond poorly to primary mRNA COVID-19 vaccination. A third dose has been shown to boost protection against severe disease and death in this immunosenescent population, but limited data is available on the immune responses it induces. METHODS: In this observational cohort study, peak humoral and cellular immune responses were compared 28 days after the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in residents and staff members of two Belgian nursing homes. Only individuals without evidence of previous SARS-CoV-2 infection at third dose administration were included in the study. In addition, an extended cohort of residents and staff members was tested for immune responses to a third vaccine dose and was monitored for vaccine breakthrough infections in the following six months. The trial is registered on ClinicalTrials.gov (NCT04527614). FINDINGS: All included residents (n = 85) and staff members (n = 88) were SARS-CoV-2 infection naïve at third dose administration. Historical blood samples from 28 days post second dose were available from 42 residents and 42 staff members. Magnitude and quality of humoral and cellular immune responses were strongly boosted in residents post third compared to post second dose. Increases were less pronounced in staff members than in residents. At 28 days post third dose, differences between residents and staff had become mostly insignificant. Humoral, but not cellular, responses induced by a third dose were predictive of subsequent incidence of vaccine breakthrough infection in the six months following vaccination. INTERPRETATION: These data show that a third dose of mRNA COVID-19 vaccine largely closes the gap in humoral and cellular immune response observed after primary vaccination between NH residents and staff members but suggest that further boosting might be needed to achieve optimal protection against variants of concern in this vulnerable population group.

Humoral and cellular immune correlates of protection against COVID-19 in kidney transplant recipients.

As solid organ transplant recipients are at high risk of severe COVID-19 and respond poorly to primary SARS-CoV-2 mRNA vaccination, they have been prioritized for booster vaccination. However, an immunological correlate of protection has not been identified in this vulnerable population. We conducted a prospective monocentric cohort study of 65 kidney transplant recipients who received 3 doses of BNT162b2 mRNA vaccine. Associations among breakthrough infection (BTI), vaccine responses, and patient characteristics were explored in 54 patients. Symptomatic COVID-19 was diagnosed in 32% of kidney transplant recipients during a period of 6 months after booster vaccination. During this period, SARS-CoV-2 delta and omicron were the dominant variants in the general population. Univariate Analyses identified the avidity of SARS-CoV-2 receptor binding domain binding IgG, neutralizing antibodies, and SARS-CoV-2 S2-specific interferon gamma responses as correlates of protection against BTI. No demographic or clinical parameter correlated with the risk of BTI. In multivariate analysis, the risk of BTI was best predicted by neutralizing antibody and S2-specific interferon gamma responses. In conclusion, T cell responses may help compensate for the suboptimal antibody response to booster vaccination in kidney transplant recipients. Further studies are needed to confirm these findings.

Safety and immunogenicity of a reduced dose of the BNT162b2 mRNA COVID-19 vaccine (REDU-VAC): A single blind, randomized, non-inferiority trial.

Fractional dosing of COVID-19 vaccines could accelerate vaccination rates in low-income countries. Dose-finding studies of the mRNA vaccine BNT162b2 (Pfizer-BioNTech) suggest that a fractional dose induces comparable antibody responses to the full dose in people <55 years. Here, we report the safety and immunogenicity of a fractional dose regimen of the BNT162b2 vaccine. REDU-VAC is a participant-blinded, randomised, phase 4, non-inferiority study. Adults 18-55 years old, either previously infected or infection naïve, were randomly assigned to receive 20µg/20µg (fractional dose) or 30µg/30µg (full dose) of BNT162b2. The primary endpoint was the geometric mean ratio (GMR) of SARS-CoV-2 anti-RBD IgG titres at 28 days post second dose between the reduced and full dose regimens. The reduced dose was considered non-inferior to the full dose if the lower limit of the two-sided 95% CI of the GMR was >0.67. Primary analysis was done on the per-protocol population, including infection naïve participants only. 145 participants were enrolled and randomized, were mostly female (69.5%), of European origin (95%), with a mean age of 40.4 years (SD 7.9). At 28 days post second dose, the geometric mean titre (GMT) of anti-RBD IgG of the reduced dose regimen (1,705 BAU/mL) was not non-inferior to the full dose regimen (2,387 BAU/mL), with a GMR of 0.714 (two-sided 95% CI 0.540-0.944). No serious adverse events occurred. While non-inferiority of the reduced dose regimen was not demonstrated, the anti-RBD IgG titre was only moderately lower than that of the full dose regimen and, importantly, still markedly higher than the reported antibody response to the licensed adenoviral vector vaccines. These data suggest that reduced doses of the BNT162b2 mRNA vaccine may offer additional benefit as compared to the vaccines currently in use in most low and middle-income countries, warranting larger immunogenicity and effectiveness trials. Trial Registration: The trial is registered at ClinicalTrials.gov (NCT04852861).

Insights From Early Clinical Trials Assessing Response to mRNA SARS-CoV-2 Vaccination in Immunocompromised Patients.

It is critical to protect immunocompromised patients against COVID-19 with effective SARS-CoV-2 vaccination as they have an increased risk of developing severe disease. This is challenging, however, since effective mRNA vaccination requires the successful cooperation of several components of the innate and adaptive immune systems, both of which can be severely affected/deficient in immunocompromised people. In this article, we first review current knowledge on the immunobiology of SARS-COV-2 mRNA vaccination in animal models and in healthy humans. Next, we summarize data from early trials of SARS-COV-2 mRNA vaccination in patients with secondary or primary immunodeficiency. These early clinical trials identified common predictors of lower response to the vaccine such as anti-CD19, anti-CD20 or anti-CD38 therapies, low (naive) CD4+ T-cell counts, genetic or therapeutic Bruton tyrosine kinase deficiency, treatment with antimetabolites, CTLA4 agonists or JAK inhibitors, and vaccination with BNT162b2 versus mRNA1273 vaccine. Finally, we review the first data on third dose mRNA vaccine administration in immunocompromised patients and discuss recent strategies of temporarily holding/pausing immunosuppressive medication during vaccination.