Immunogenicity Trial Research Articles

Bivalent RSVpreF Vaccine in Adults 18 to

Older individuals and adults with certain chronic or immunocompromising health conditions are at increased risk of severe RSV disease. In this phase 3 randomized trial of RSVpreF safety and immunogenicity in 18-59-year-olds at high-risk of severe RSV disease, participants were randomized 2:1 to 1 RSVpreF (120 µg) or placebo dose. Primary safety endpoints included reactogenicity events and adverse events (AEs) through 7 days and 1 month after vaccination, respectively, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) throughout the study. In primary analyses, immunogenicity elicited 1 month after RSVpreF was bridged to a randomly selected subset of ≥60-year-olds receiving RSVpreF from the immunogenicity subset in the pivotal phase 3 RENOIR trial, which demonstrated RSVpreF efficacy. Noninferiority was declared if 95% CI lower bounds were >0.667 (neutralizing titer adjusted geometric mean ratios) and >-10% (seroresponse rate differences) for RSV-A and RSV-B. Overall, 678 participants received RSVpreF (n=453) or placebo (n=225). Most reactogenicity events were mild/moderate; severe events occurred in ≤2.0% of participants overall. AE frequencies were similar in RSVpreF (7.1%) and placebo recipients (7.6%). No vaccine-related SAEs or NDCMCs were reported. One month after RSVpreF administration, noninferiority criteria were met in 18-59-year-olds versus ≥60-year-olds for RSV-A and RSV-B neutralizing titers and seroresponse rates. RSVpreF was well tolerated with no safety concerns and demonstrated immunobridging to efficacy in 18-59-year-olds at high-risk of severe RSV disease versus ≥60-year-olds in whom efficacy was previously demonstrated, supporting use of RSVpreF to prevent RSV-associated disease in this population. NCT05842967.

Randomised immunogenicity trial comparing 2019-2020 recombinant and egg-based influenza vaccines among frequently vaccinated healthcare personnel in Israel

ObjectivesTrivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016 to 2019. We conducted a randomised immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants. MethodsFrom October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titres against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titre (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 vs ≤2). ResultsAmong 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titres than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0). ConclusionRIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4. Clinical trials registrationNCT04523324

A phase I dose escalation trial of BCD-145 in patients with unresectable or metastatic melanoma.

9526 Background: BCD-145 (nurulimab) is a fully human IgG1 mAb with modified Fc-fragment (the 1st Gln is replaced by Glu in the heavy chain sequence, and there is no terminal dipeptide composed by Gly and Lys residues) that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction between CTLA-4 and its ligands. This allows to stimulate T-cell proliferation, cytokine production and induces antitumor immune response. Here we present the results of multicenter open-label single-arm multi-cohort phase I trial of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity of BCD-145 in pts with unresectable/metastatic melanoma (unr/mM). Methods: BCD-145 monotherapy in 3+3 dose escalation [0.1, 0.3, 1, 3, 10 mg/kg intravenously Q3W] was given to 15 pts with unr/mM with measurable disease, who had failed prior therapy, ECOG 0-2. Pts with brain mts, previous therapy with aCTLA-4 and/or aPD-1/PD-L1 drugs were not allowed. The main objective of the study was to evaluate PK, PD, tolerability, immunogenicity, safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) identification. Secondary objectives included tumor response rate (irRECIST). Results: BCD-145 proved safety and overall was well tolerated. DLT and MTD were not reached. Any grade (Gr) adverse events (AEs) occurred in 100% (15/15) of pts. 33.3% (5/15) of pts had AE/SAE of Gr 3-4, including hypertension Gr 3 (1 at 1 mg/kg), hypercalcemia Gr 4 (2 at 1 mg/kg), hypokalemia Gr 3 (2 at 1 mg/kg), neutropenia Gr 3 (1 at 0.3 mg/kg), anemia Gr 3 (1 at 1 mg/kg), lung infection Gr 3 with hospitalization (1 at 1 mg/kg). Only 2 pts had a treatment-related AE Gr 3-4. Immuno-related AE were identified in 46.7% (7/15), manifested by symptoms of thyroiditis (mainly Gr 1) and diarrhea Gr 2 (1 at 10 mg/kg). There was 1 death (at 1 mg/kg) due to progression. There is dose-dependent peak study drug serum concentrations and systemic exposure. Two dosage regimens (1 mg/kg, 3 mg/kg Q3W) allowed to achieve the optimal concentration. BCD-145 increased subpopulations of activated HLA-DR+ CD4+ and CD8+ T lymphocytes, CD4+ICOS+ T-lymphocytes, absolute lymphocyte counts in all cohorts without significant differences. Binding and neutralizing Abs against BCD-145 were detected in 2 pts from different dose cohorts (0.3 mg/kg, 1 mg/kg). PR and SD were registered in 2 pts of each response group. 30.8% of pts achieved disease control, which is consistent with published data on other CTLA-4 inhibitors. A dose of 1 mg/kg is determined as recommended phase 2 dose (RP2D). Conclusions: BCD-145 demonstrated a tolerable safety profile and preliminary anti-tumor activity in pts with unr/mM. Anti-tumor effects of BCD-145 were observed in pts who had progressed on prior treatment. Further co-targeting PD-1 and CTLA-4 simultaneously will achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Clinical trial information: NCT03472027 .

Clinical trial of tolerability, safety and immunogenicity of influenza inactivated split-vaccine Flu-M in children aged 6 to 17 years

Purpose. To evaluate the tolerability, safety and immunogenicity of influenza inactivated split flu vaccine Flu-M during single immunization of children aged 6 to 17 years.Materials and methods. A multicentre double-blind comparative randomised clinical trial of influenza inactivated split vaccine Flu-M for immunisation of children aged 6 to 17 years (the reference agent – Ultrix vaccine) was conducted. Children aged 12 to 17 years inclusive (300 children) were studied at stage I, and children aged 6 to 12 years (300 children) at stage II. Volunteers of each age category were randomised 1:1 into 2 groups comparable in sex and age, one was vaccinated with Flu-M vaccine and the other with Ultrix vaccine. The follow-up, including various laboratory and clinical tests, lasted for 28 days from the time of vaccination.Results. Both vaccines were well tolerated by children aged 12 to 17 years and by children aged 6 to 12 years. There were no severe or serious adverse events. By all criteria of immunogenicity evaluation, vaccine Flu-M was not inferior to the comparison vaccine Ultrix.Conclusion. Influenza inactivated split Flu-M vaccine produced by SPbNIIVS is approved for use for specific prophylaxis of influenza in children aged 6 to 17 years in the Russian Federation, the Republic of Belarus, Latin America and the Caribbean.The trial is registered at ClinicalTrials. gov (NCT 05317767).

A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults

BackgroundTo improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. MethodsA double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). ResultsSubjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3–63), versus separate arms (57.4 µg/mL: 95 % CI 32.3–102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8–101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had ∼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. ConclusionCo-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. ClinicalTrials.gov identifier: NCT01556945.

Perceptions, attitudes, and willingness of healthcare and frontline workers to participate in an Ebola vaccine trial in Uganda

BackgroundUnderstanding the knowledge, perception and attitudes towards Ebola vaccines is an important factor in ensuring future use of these vaccines. A qualitative methods study embedded in an Ebola vaccine immunogenicity and safety trial (NCT04028349) was conducted to explore the knowledge and perceptions of healthcare (HCWs) and frontline workers (FLWs), about Ebola vaccines and their willingness to participate or recommend participation in Uganda. MethodWe carried out focus group discussions and semi-structured interviews before and after vaccination, with 70 HCWs and FLWs who consented to participate in the trial, and in the qualitative component, from August to September 2019. Data were analysed using thematic content analysis. ResultsRespondents showed good knowledge about Ebola and the vaccines in general, and had wide access to information through several channels, including the study team. On prevention, particular attention was given to effective communication within health facilities. Misconceptions were mainly around route of transmission, animal origin and types of vaccines. Previous fears were based on rumours circulating in the community, mainly about the presence of the virus in the vaccine, side effects and intention to harm (e.g. by “the whites”), ultimately insisting on transparency, trust and involvement of local leaders. Acceptability of participation was motivated by the need to protect self and others, and the willingness to advance research. Majority were willing to recommend participation to their community. ConclusionsOverall, information sharing leads to a better understanding and acceptance of vaccine trials and a positive vaccination experience can be a deciding factor in the acceptance of others. Particular attention should be paid to involving the community in addressing misconceptions and fears, while ensuring that participants have access to vaccination sites in terms of transport, and that they are properly accommodated at the study site including staying for a reasonable period of time.

Immunogenicity of 2-Dose HPV Vaccine Series for Postpartum Women

Postpartum human papillomavirus (HPV) vaccination is a promising strategy to increase HPV vaccination uptake in the US, particularly for reaching vaccine-naive women and those who lack health insurance beyond the pregnancy period. However, completion of the 3-dose vaccine regimen is challenging. To evaluate the immunogenicity of a 2-dose postpartum HPV vaccination regimen (0 and 6 months) and assess whether it is noninferior to a 3-dose postpartum HPV vaccination regimen (0, 1-2, and 6 months) administered to historical controls. A noninferiority, open-label, nonrandomized immunogenicity trial was conducted from August 4, 2020, to June 23, 2022, of postpartum patients aged 15 to 45 years who delivered at 2 hospitals in Baltimore, Maryland. Historical controls were adolescents and young women aged 16 to 26 years. Two doses of the nonavalent HPV vaccine administered 6 months apart. The primary outcome was noninferiority (90% CI, lower bound >0.67) of the geometric mean titer (GMT) ratio for HPV-16 among postpartum women compared with historical controls. Secondary outcomes were noninferiority of GMT ratios for the other 8 HPV types and percentage seroconversion for each HPV type. As a noninferiority trial, the primary analysis used the per-protocol analysis. Of 225 enrolled participants, the mean (SD) age at baseline was 29.9 (6.8) years, and 171 (76.0%) were HPV-16 seronegative at baseline. Of these 171 participants, 129 (75.4%) received a second vaccine dose and completed the subsequent 4-week serologic measurements. Relative to historical controls, the HPV-16 GMT ratio was 2.29 (90% CI, 2.03-2.58). At month 7, HPV-16 GMT was higher after the 2-dose regimen (7213.1 mMU/mL [90% CI, 6245.0-8331.4 mMU/mL]) than among historic controls after the 3-dose regimen (3154.0 mMU/mL [90% CI, 2860.2-3478.0 mMU/mL]). Similarly, the lower bound of the 90% CI of the GMT ratio was above 1 for the 8 HPV types 6, 11, 18, 31, 33, 45, 52, and 58. A total of 118 of 134 women (88.1%) seroconverted for HPV-16 after the first dose; 4 weeks after the second dose, the seroconversion rate was 99% or greater for all HPV types. This study suggests that immunogenicity of a 2-dose HPV vaccination regimen given 6 months apart among postpartum women was noninferior to a 3-dose regimen among young historical controls. Most women seroconverted after the first dose of the 2-dose regimen. These results demonstrate that postpartum vaccination using a reduced schedule may be a promising strategy to increase HPV vaccine series completion. ClinicalTrials.gov Identifier: NCT04274153.

Estimand for non-inferiority influenza vaccine immunogenicity trials

According to recent regulatory guidance, clinical trial objectives should be translated into estimands, i.e., precise descriptions of that what is to be estimated. Hence, estimands are to be formulated for influenza vaccine immunogenicity (IVI) trials, notably for one of the most popular immunogenicity trials, the non-inferiority trial. In this paper an estimand for this trial design is proposed.An estimand should state how intercurrent events are handled. Intercurrent events are events that occur after the start of the trial and that affect the endpoint’s measurement or interpretation or prevent its observation. In IVI trials the intercurrent events of interest are immunological intercurrent events (IIEs). Major IIEs are identified, i.e., protocol deviations occurring during the trial that affect immunogenicity endpoints, and the consequences for the trial data collection are discussed.In the statistical analysis endpoint values that are missing or excluded from the analysis due to IIEs are to be substituted by plausible values, by means of multiple imputing. Replacing values are based on predictors of the endpoint. A distinction is made between mandatory and non-mandatory predictors. Mandatory predictors are predictors necessary to prevent biased prediction. Non-mandatory predictors are predictors that limit the additional variance due to the imputing. The four steps of the multiple imputing are explained, and available software is listed.

Clinical trial of tolerability, safety, and immunogenicity of the Russian influenza inactivated split vaccine Flu-m in children from 6 months to 9 years of age

Purpose: To study the reactogenicity, safety and immunogenicity of the Russian vaccine Flu-M in comparison with Vaxigrip vaccine for influenza prevention in children aged from 6 months to 9 years (phase III).Materials and Methods. In 2021, a clinical study was conducted in which children aged 6 months to 9 years were immunized with Flu-M vaccine (produced by SPbSRIVS, Russia) and Vaxigrip vaccine (produced by Sanofi Pasteur S.A., France). After randomization one group of children was vaccinated with Flu-M, the other with Vaxigrip, and monitored for 180±3 days after vaccination. Children vaccinated between 3 and 9 years of age were studied in phase I, and between 6 months and 3 years of age in phase II. Tolerability and safety were assessed by the frequency and extent of adverse events, as well as by the assessment of vital signs and physical examination. Immunological efficacy assessment criteria were geometric mean antibody titer, seroconversion level, seroconversion factor, seroprotection level.Results. Both vaccines (Flu-M and Vaxigrip) were shown to be well tolerated by children of both age groups. No serious adverse events or severe adverse events were reported in the study. Immunological efficacy criteria were achieved for both vaccines for all strains of influenza virus in children of both age groups at 28 and 56 days after vaccination. No cases of influenza or acute respiratory infections were seen at 180±3 days postvaccination.Conclusion. The results of the clinical study show that the Flu-M and Vaxigrip vaccines are comparable in both age groups of children.The trial is registered at ClinicalTrials.gov (NCT 05470582).

Pneumococcal carriage following PCV13 delivered as one primary and one booster dose (1+1) compared to two primary doses and a booster (2+1) in UK infants.

In January 2020 the UK changed from a 2+1 schedule for 13-valent pneumococcal conjugate vaccine (PCV13) to a 1+1 schedule (doses at 3 and 12months) based on a randomized immunogenicity trial comparing the two schedules. Carriage prevalence measured at the time of booster and 6months later in 191 of the 213 study infants was 57% (109/191) and 60% (114/190) respectively. There were eight episodes of vaccine-type (VT) or vaccine-related 6C carriage in the 2+1 and six in the 1+1 group; ≥4-fold rises in serotype-specific IgG in 71 children with paired post-booster and follow up blood samples at 21-33months of age were found in 20% (7/35) of the 2+1 and 15% (6/41) of the 1+1 group. VTs identified in carriage and inferred from serology were similar comprising 3, 19A and 19F. Dropping a priming dose from the 2+1 PCV 13 schedule did not increase VT carriage in the study cohort. Ongoing population level carriage studies will be important to confirm this.

Phase II randomized, double blind, placebo controlled, clinical trial of safety and immunogenicity of an inactivated SARS-CoV-2 vaccine FAKHRAVAC in adults aged 18–70 years

BackgroundThe FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity in a phase II trial.MethodsWe did a phase II, single-centered, randomized, double-blind, placebo-controlled clinical trial of the FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The two parallel groups received two intramuscular injections of either a 10-µg vaccine or a placebo at 2-week intervals. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were compared over the study period of up to 6 months. Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels.ResultsFive hundred eligible participants were randomly (1:1) assigned to vaccine or placebo groups. The median age of the participants was 36 years, and 75% were male. The most frequent local adverse reaction was tenderness (21.29% after the first dose and 8.52% after the second dose), and the most frequent systemic adverse reaction was headache (11.24% after the first dose and 8.94% after the second dose). Neutralizing antibody titers two and four weeks after the second injection in the vaccine group showed about 3 and 6 times increase compared to the placebo group (GMR = 2.69, 95% CI 2.32–3.12, N:309) and (GMR = 5.51, 95% CI 3.94–8.35, N:285). A four-fold increase in the neutralizing antibody titer was seen in 69.6% and 73.4% of the participants in the vaccine group two and four weeks after the second dose, respectively. Specific ELIZA antibody response against a combination of S1 and RBD antigens 4 weeks after the second injection increased more than three times in the vaccine compared to the placebo group (GMR = 3.34, 95% CI 2.5–4.47, N:142).ConclusionsFAKHRAVAC® is safe and induces a significant humoral immune response to the SARS-CoV-2 virus at 10-µg antigen dose in adults aged 18–70. A phase III trial is needed to assess the clinical efficacy.Trial registration: Trial Registry Number: Ref., IRCT20210206050259N2 (http://irct.ir; registered on 08/06/2021)

Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age

BackgroundSafe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children.MethodsWe conducted a phase 1 dose-finding study and are conducting an ongoing phase 2–3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2–3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-μg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-μg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 μg of BNT162b2 in the pivotal trial.ResultsDuring the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-μg dose) and 48 children 2 to 4 years of age (3-μg or 10-μg dose). The 3-μg dose level was selected for the phase 2–3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases).ConclusionsA three-dose primary series of 3-μg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.)

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).

Immunological non-inferiority and safety of a quadrivalent inactivated influenza vaccine versus two trivalent inactivated influenza vaccines in China: Results from two studies

ABSTRACT A quadrivalent, split-virion influenza vaccine (Shz QIV), containing two influenza A strains, and both B lineages strains, has been developed in China. We report the safety and immunogenicity of Shz QIV in two studies: a single-center, phase I, open-label, safety trial (n = 101) and a multicenter, phase III, observer-blind, randomized, safety and immunogenicity trial (n = 7,106) comparing Shz QIV with two trivalent influenza vaccines (Shz TIVs; one containing a B/Victoria-like strain and the other a B/Yamagata-like strain). Participants received one dose of Shz QIV (0.5 mL), except children aged 6 months to 8 years who received one or two doses (0.25 mL or 0.5 mL) depending on previous influenza vaccination. The Shz TIV groups received one or two (0.25 mL) doses depending on previous influenza vaccination (ages 6–35 months) or a single (0.5 mL) dose (ages ≥3 years). Immunogenicity was assessed at baseline and 28 days after the last dose, with safety assessed through to 6 months. The primary objective was to demonstrate the non-inferiority of antibody responses to Shz QIV (0.25 mL and 0.5 mL) versus Shz TIVs for each strain in ages 6–35 months and ≥3 years. Overall, Shz QIV was well tolerated, and showed similar safety to the Shz TIVs. Shz QIV (0.5 mL) induced non-inferior antibody responses to all antigens versus Shz TIV, with superiority demonstrated to the non-corresponding B strain in each TIV. Shz QIV (0.25 mL) non-inferiority in those aged 6–35 months was demonstrated for both A strains and the B/Yamagata-like strain, but not the B/Victoria-like strain. In summary, Shz QIV (0.5 mL) is immunogenic and has a good safety profile. WHO Universal Trial Numbers (UTNs) U1111-1174-4615 and U1111-1174-4698 ClinicalTrials.gov NCT04210349 and NCT03430089

Effect of Repeat Vaccination on Immunogenicity of Quadrivalent Cell-Culture and Recombinant Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years: A Randomized, Open-Label Trial.

Antibody responses to non-egg-based standard-dose cell-culture influenza vaccine (containing 15 µg hemagglutinin [HA]/component) and recombinant vaccine (containing 45 µg HA/component) during consecutive seasons have not been studied in the United States. In a randomized trial of immunogenicity of quadrivalent influenza vaccines among healthcare personnel (HCP) aged 18-64 years over 2 consecutive seasons, HCP who received recombinant-HA influenza vaccine (RIV) or cell culture-based inactivated influenza vaccine (ccIIV) during the first season (year 1) were re-randomized the second season of 2019-2020 (year 2 [Y2]) to receive ccIIV or RIV, resulting in 4 ccIIV/RIV combinations. In Y2, hemagglutination inhibition antibody titers against reference cell-grown vaccine viruses were compared in each ccIIV/RIV group with titers among HCP randomized both seasons to receive egg-based, standard-dose inactivated influenza vaccine (IIV) using geometric mean titer (GMT) ratios of Y2 post-vaccination titers. Y2 data from 414 HCP were analyzed per protocol. Compared with 60 IIV/IIV recipients, 74 RIV/RIV and 106 ccIIV/RIV recipients showed significantly elevated GMT ratios (Bonferroni corrected P < .007) against all components except A(H3N2). Post-vaccination GMT ratios for ccIIV/ccIIV and RIV/ccIIV were not significantly elevated compared with IIV/IIV except for RIV/ccIIV against A(H1N1)pdm09. In adult HCP, receipt of RIV in 2 consecutive seasons or the second season was more immunogenic than consecutive egg-based IIV for 3 of the 4 components of quadrivalent vaccine. Immunogenicity of ccIIV/ccIIV was similar to that of IIV/IIV. Differences in HA antigen content may play a role in immunogenicity of influenza vaccination in consecutive seasons. NCT03722589.

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

BackgroundPriming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca).MethodsCom-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33).FindingsBetween Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules.InterpretationThese data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals.FundingUK Vaccine Taskforce and National Institute for Health and Care Research.

Plasma VP8∗-Binding Antibodies in Rotavirus Infection and Oral Vaccination in Young Bangladeshi Children.

BackgroundDespite the availability and success of live-attenuated oral vaccines, rotavirus (RV) remains the leading cause of pediatric gastroenteritis worldwide. Next-generation vaccines targeting RV VP8∗ are under evaluation, but the role of VP8∗-specific antibodies in human immunity to RV and their potential as immune correlates of protection remains underexplored.MethodsWe measured plasma RV VP8∗-binding antibodies in 2 cohorts of young children in Dhaka, Bangladesh. Plasma from a cohort study of 137 unvaccinated children aged 6-24 months old hospitalized with acute gastroenteritis was assessed for VP8∗ antibody seropositivity. VP8∗ antibodies were compared with the current standard for RV immunity, total RV-specific IgA (RV-IgA). Additionally, VP8∗ antibody responses were measured as part of an immunogenicity trial of a monovalent, oral, live-attenuated RV vaccine (Rotarix).ResultsFewer children with acute RV gastroenteritis were seropositive for VP8∗-binding IgA or IgG antibodies at hospital admission compared with RV-IgA, suggesting that the absence of VP8∗-binding antibodies more accurately predicts susceptibility to RV gastroenteritis than RV-IgA in unvaccinated children. However, when present, these antibodies appeared insufficient to protect fully from disease and no threshold antibody level for protection was apparent. In vaccinated children, these antibodies were very poorly induced by Rotarix vaccine, suggesting that VP8∗-specific antibodies alone are not necessary for clinical protection following oral vaccination.ConclusionsThis work suggests that VP8∗-binding antibodies may not be sufficient or necessary for protection from RV gastroenteritis following prior RV infection or oral vaccination; the role of VP8∗ antibodies induced by parenteral vaccination with non-replicating vaccines remains to be determined.

A phase 2 randomized controlled dose-ranging trial of recombinant pertussis booster vaccines containing genetically inactivated pertussis toxin in women of childbearing age

BackgroundA phase 2 randomized-controlled safety and immunogenicity trial evaluating different doses of recombinant acellular pertussis vaccine containing genetically-inactivated pertussis toxin (PTgen) was conducted in women of childbearing age in Thailand to identify formulations to advance to a trial in pregnant women. MethodsA total of 250 women were randomized 1:1:1:1:1 to receive one dose of one of three investigational vaccines including low-dose recombinant pertussis-only vaccine containing 1 μg PTgen and 1 μg FHA (ap1gen), tetanus, reduced-dose diphtheria (Td) combined to ap1gen (Tdap1gen) or combined to recombinant pertussis containing 2 μg PTgen and 5 μg FHA (Tdap2gen), or one dose of licensed recombinant TdaP vaccine containing 5 μg PTgen and 5 μg FHA (Boostagen®, TdaP5gen) or licensed Tdap vaccine containing 8 μg of chemically inactivated pertussis toxoid (PTchem), 8 μg FHA, and 2.5 μg pertactin (PRN) (BoostrixTM, Tdap8chem). Serum Immunoglobulin G (IgG) antibodies against vaccine antigens were measured before and 28 days after vaccination by ELISA. To advance to a trial in pregnant women, formulations had to induce a PT-IgG seroresponse rate with a 95% confidence interval (95% CI) lower limit of ≥ 50%. ResultsBetween 5 and 22 July 2018, a total of 250 women with median age of 31 years were enrolled. Post-vaccination PT-IgG seroresponse rates were 92% (95% CI 81–98) for ap1gen, 88% (95% CI 76–95) for Tdap1gen, 80% (95% CI 66–90) for Tdap2gen, 94% (95% CI 83–99) for TdaP5gen, and 78% (95% CI 64–88) for Tdap8chem. Frequencies of injection site and systemic reactions were comparable between the groups. No serious adverse events were reported during the 28-day post-vaccination period. ConclusionsAll recombinant acellular pertussis vaccines were safe and immunogenic in women of childbearing age, and all met pre-defined immunogenicity criteria to advance to a trial in pregnant women.Clinical Trial Registration: Thai Clinical Trial Registry, TCTR20180321004.

Covaxin: An overview of its immunogenicity and safety trials in India.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a global coronavirus disease-19 (COVID-19) pandemic. Several vaccine types, such as inactivated, viral vector-, or mRNA-based, have received approval against SARS-CoV-2. The ability to induceT-helper-1 cell (Th1) responses is desirable from an effective vaccine against this virus. Covaxin (BBV152) is a wholevirion inactivated SARS-CoV-2 vaccine adjuvanted with Algel-Imidazoquinoline (IMDG) molecule, a toll-like receptor (TLR) 7/8 agonist. The mRNA-based vaccine use is hindered because of cold storage requirement, whereas covaxin is stored between 2°C and 8°C, making it suitable for countries with limited resources. The Drug Controller General of India (DCGI) has approved the BBV152 vaccine. Therefore, it is of interest to document known data on BBV152 vaccine phase I, phase II and phase III human clinical trials to evaluate the safety, reactogenicity, tolerance, and immunogenicity of the whole-virion inactivated SARS-CoV-2 vaccine (BBV152).

Immunogenicity of the Oral Rabies Vaccine Strain SPBN GASGAS in Dogs Under Field Settings in Namibia.

Dog-mediated rabies is endemic throughout Africa. While free-roaming dogs that play a crucial role in rabies transmission are often inaccessible for parenteral vaccination during mass dog vaccination campaigns, oral rabies vaccination (ORV) is considered to be a promising alternative to increase vaccination coverage in these hard-to-reach dogs. The acceptance of ORV as an efficient supplementary tool is still low, not least because of limited immunogenicity and field trial data in local dogs. In this study, the immunogenicity of the highly attenuated 3rd-generation oral rabies vaccine strain SPBN GASGAS in local free-roaming dogs from Namibia was assessed by determining the immune response in terms of seroconversion for up to 56 days post-vaccination. At two study sites, free-roaming dogs were vaccinated by administering the vaccine either by direct oral administration or via a vaccine-loaded egg bait. Pre- and post-vaccination blood samples were tested for rabies virus neutralizing as well as binding antibodies using standard serological assays. A multiple logistic regression (MLR) analysis was performed to determine a possible influence of study area, vaccination method, and vaccine dose on the seroconversion rate obtained. About 78% of the dogs vaccinated by the oral route seroconverted (enzyme-linked immunosorbent assay, ELISA), though the seroconversion as determined by a rapid fluorescence focus inhibition test (RFFIT) was much lower. None of the factors examined had a significant effect on the seroconversion rate. This study confirms the immunogenicity of the vaccine strain SPBN GASGAS and the potential utility of ORV for the control of dog-mediated rabies in African dogs.