Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised, placebo-controlled, multicentre Phase II clinical trial

Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.gov NCT02564523.

Comparison of infectious SARS-CoV-2 from the nasopharynx of vaccinated and unvaccinated individuals

The frequency of SARS-CoV-2 breakthrough infections in fully vaccinated individuals increased with the emergence of the Delta variant, particularly with longer time from vaccine completion. However, whether breakthrough infections lead to onward transmission remains unclear. Here, we conducted a study involving 125 patients comprised of 72 vaccinated and 53 unvaccinated individuals, to assess the levels of infectious virus in in vaccinated and unvaccinated individuals. Quantitative plaque assays showed no significant differences in the titers of virus between these cohorts. However, the proportion of nasopharyngeal samples with culturable virus was lower in the vaccinated patients relative to unvaccinated patients (21% vs. 40%). Finally, time-to-event analysis with Kaplan-Myer curves revealed that protection from culturable infectious virus waned significantly starting at 5 months after completing a 2-dose regimen of mRNA vaccines. These results have important implications in timing of booster dose to prevent onward transmission from breakthrough cases.

Immunogenicity of heterologous BNT162b2 booster in fully vaccinated individuals with CoronaVac against SARS-CoV-2 variants Delta and Omicron: the Dominican Republic Experience

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and by its numerous spike mutations with potential to evade neutralizing antibodies elicited by COVID-19 vaccines. The Dominican Republic was among the first countries in recommending the administration of a third dose COVID-19 vaccine to address potential waning immunity and reduced effectiveness against variants. Here, we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants that had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that heterologous CoronaVac prime followed by BNT162b2 booster regimen induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and Delta variant, resembling the titers obtained after two doses of mRNA vaccines. While neutralization of Omicron was undetectable in participants that had received a two-dose regimen of CoronaVac vaccine, BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron, compared to two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 6.3-fold and 2.7-fold for Omicron compared to ancestral and Delta variant, respectively. Surprisingly, previous SARS-CoV-2 infection did not affect the neutralizing titers for Omicron in participants that received the heterologous regimen. Our findings have immediate implications for multiples countries that previously used a two-dose regimen of CoronaVac and reinforce the notion that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.

Effectiveness of BNT162b2 and mRNA-1273 Second Doses and Boosters for SARS-CoV-2 infection and SARS-CoV-2 Related Hospitalizations: A Statewide Report from the Minnesota Electronic Health Record Consortium

Using vaccine data combined with electronic health records, we report that mRNA boosters provide greater protection than a two-dose regimen against SARS-CoV-2 infection and related hospitalizations. The benefit of a booster was more evident in the elderly and those with comorbidities. These results support the case for COVID-19 boosters.

Immunogenicity of heterologous prime/boost inactivated and mRNA COVID-19 vaccine

Introduction: In August 2021, Thailand imported the BNT162b2 mRNA COVID-19 vaccine. The prioritised group to receive the BNT162b2 vaccine were health professionals. The BNT162b2 vaccine scheduled for healthcare workers were two-dose regimen administered three weeks apart, the third dose booster in two-dose inactivated CoronaVac vaccine recipients or as a second dose in health professionals who had received the CoronaVac or adenoviral-vectored (ChAdOx1-S) vaccine as the first dose regardless of the interval between the first and second dose. Methods: This study aims to evaluate the immunogenicity of the heterologous prime boost CoronaVac followed by BNT162b2 in health professionals. Results: The CoronaVac/BNT162b2 vaccine recipients elicited higher neutralizing activity against the original Wuhan and all variants of concern than in the recipients of the two-dose CoronaVac. Conclusions: The heterologous CoronaVac/BNT162b2 could be used as an alternative regimen in countries experiencing the vaccine shortages and in individuals experiencing the adverse events following CoronaVac.

Optimization of Initial Dose Regimen for Sirolimus in Pediatric Patients With Lymphangioma

Sirolimus is an effective oral treatment for pediatric patients with lymphangioma. The present clinical study in 15 children (0.12–16.39 years of age) examines the effects of underlying factors on sirolimus concentrations through application of a population pharmacokinetic model. Using Monte Carlo simulation, an initial dose regimen for sirolimus in pediatric patients with lymphangioma is presented. It is found that the lower the body weight, the higher the clearance rate and sirolimus clearances are 0.31–0.17 L/h/kg in pediatric patients with lymphangioma whose weights are 5–60 kg, respectively. The doses of sirolimus, 0.07, 0.06, 0.05 mg/kg/day are recommended for weights of 5–10, 10–24.5 and 24.5–60 kg in children with lymphangioma. This study is the first to establish a population pharmacokinetic model for sirolimus and to recommend initial doses in pediatric patients with lymphangioma. Large scale, prospective studies are needed in the future.

Integrated exposure–response analysis of efficacy and safety of lurbinectedin to support the dose regimen in small-cell lung cancer

Purpose These exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m2 1-h intravenous infusion every 3 weeks (q3wk). Methods Logistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUCtot and AUCu) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients (n = 99) treated in study B-005 with 3.2 mg/m2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies (n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose. Results Effect of lurbinectedin AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range. Conclusions The relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m2 q3wk. Trial registration Clinicaltrials.gov: NCT02454972; registered May 27, 2015.

Correlation of SARS-CoV-2-breakthrough infections to time-from-vaccine

The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine was widely demonstrated. However, long term effectiveness is still unknown. Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we assessed the correlation between time-from-vaccine and incidence of breakthrough infection between June 1 and July 27, the date of analysis. After controlling for potential confounders as age and comorbidities, we found a significant 1.51 fold (95% CI, 1.38–1.66) increased risk for infection for early vaccinees compared to those vaccinated later that was similar across all ages groups. The increased risk reached 2.26- fold (95% CI, 1.80–3.01) when comparing those who were vaccinated in January to those vaccinated in April. This preliminary finding of vaccine waning as a factor of time from vaccince should prompt further investigations into long-term protection against different strains.