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Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 μg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 μg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 μg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

In a phase 3 trial, adults (≥60 years of age) received one 120-μg dose of RSVpreF vaccine (17,215) or placebo (17,069). Vaccine efficacy against RSV-associated lower respiratory tract illness was 67 to 86%.

Pneumococcal conjugate vaccines (PCVs) are generally administered in infant schedules with other vaccines. Here, we describe the safety and immunogenicity of routinely recommended pediatric vaccines given with 20-valent-PCV (PCV20). Two phase 3, double-blind, randomized trials evaluated the safety, tolerability, and immunogenicity of PCV20 in infants with concomitant pediatric vaccines. The studies examined a 4-dose series (Study B7471011/NCT04382326; N = 1997) and a 3-dose series (Study B7471012/NCT04546425; N = 1207). Concomitant vaccinations included a combination vaccine (diphtheria, tetanus, acellular pertussis [DTaP] with hepatitis B and poliovirus antigens (DTaP-HBV-IPV) and Haemophilus influenzae type b vaccine [Hib]) in Study B7471011 or combined vaccine (DTaP, hepatitis B, poliovirus, and Hib antigens [DTaP-HBV-IPV/Hib]) in Study B7471012. Measles, mumps, rubella (MMR) and varicella vaccines were given concomitantly with the toddler dose in both studies. Immunogenicity objectives were to demonstrate noninferiority of immune responses to concomitant vaccine antigens for concomitant vaccines given with PCV20 to those given with 13-valent PCV (PCV13). Safety endpoints included systemic events and adverse events (AEs). Noninferiority was met for the primary objectives of percentage of participants with prespecified antibody levels to the DTaP-HBV-IPV and Hib 1 month after the third infant dose (Study B7471011) and 1 month after the toddler dose of DTaP-HBV-IPV/Hib (Study B7471012) in the PCV20 group compared with the PCV13 group. Noninferiority was also met for the geometric mean antibody levels to MMR and varicella vaccines 1 month after the toddler dose in both studies. Systemic event frequencies were similar in the PCV20 and PCV13 groups in both studies, with severity mostly reported as mild or moderate. Frequencies of reported AEs were similar between the PCV20 and PCV13 groups. Immune responses to routine pediatric vaccines given with PCV20 were noninferior to those when given with PCV13. PCV20 may be safely administered with other routine pediatric vaccines. (NCT04382326; NCT04546425). •Two phase 3, double-blind, randomized trials evaluated PCV20 in infants.•The studies included concomitant administration of routine pediatric vaccines.•Immune responses to these concomitant pediatric vaccines were evaluated.•Responses to concomitant vaccines were noninferior with PCV20 to those with PCV13.•PCV20 may be safely administered with other routine pediatric vaccines.

A multicomponent vaccine targeting several seasonal respiratory pathogens may provide simultaneous protection in a single-injection regimen. We present interim (28 days) findings from a phase 1/2 study of an mRNA-based multicomponent vaccine (mRNA-1083), encoding seasonal influenza and SARS-CoV-2 antigens. Adults (18–79 years) were randomly assigned to receive different compositions of mRNA-1083 at varying dose levels on day 1. The primary study objectives were reactogenicity through 7 days and safety through 28 days postvaccination, and the secondary study objective was immunogenicity against vaccine-matched influenza and SARS-CoV-2 strains at day 29 assessed by hemagglutination inhibition and pseudovirus neutralization assays, respectively. The multicomponent mRNA-1083 vaccine was generally well-tolerated, with most solicited adverse reactions being Grade 1 or 2 in severity. The incidence of unsolicited adverse events was similar across vaccine groups. mRNA-1083 induced immune responses against influenza and SARS-CoV-2 that were, in general, similar to or higher than those achieved with licensed quadrivalent influenza (standard or high dose) and SARS-CoV-2 (bivalent mRNA-1273) vaccines. These data support ongoing phase 3 evaluation of the mRNA-1083 vaccine. ClinicalTrials.gov registration: NCT05827926 . An interim analysis shows that a new mRNA influenza and SAR-CoV-2 combination vaccine is safe and triggers an encouraging immune response.

The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12–17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64–88) participants in the aP(PTgen/FHA) group and 41 (81%, 70–92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1–16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71–93 and 64%, 51–77, respectively) and TdaP(PTgen/FHA) group (75%, 63–87 and 56%, 42–70, respectively) than in the Tdap group (4%, 0–9, p<0·0001, and 28%, 16–41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. BioNet-Asia.

Combination vaccines are effective in simplifying complex vaccination schedules involving multiple vaccines. A fully liquid hexavalent diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)- hepatitis B (HepB)-inactivated poliovirus (IPV)-Haemophilus influenzae b (Hib) vaccine (HEXASIIL®), manufactured by Serum Institute of India Pvt. Ltd. was tested for safety and immunogenicity following booster vaccination. This was a phase-II/III, open label, multicentric, controlled trial in toddlers (phase II) and infants (phase III) in India. This manuscript presents results of phase II. Healthy toddlers aged 12–24 months were randomized (1:1) to receive a 0.5 ml booster dose of HEXASIIL® or comparator Pentavac SD + Poliovac, intramuscularly and followed for 28 days for safety assessment. Blood samples were collected pre-vaccination and 28 days post-vaccination to assess immunogenicity. Descriptive summary statistics were provided for safety and immunogenecity analyses. A total of 223 subjects were randomized. One subject droped out prior to dosing, due to consent withdrawal. Thus, 222 subjects received study vaccine (110 HEXASIIL® and 112 comparator). Frequency of solicited adverse events was comparable between HEXASIIL® and comparator (85.5 % vs 90.2 %). Most local and systemic solicited AEs were mild to moderate in severity. All events resolved completely without any sequelae and none led to subject discontinuation. No vaccine related serious AE was reported. Post vaccination, seroprotection rates against tetanus, Hib and polio type 1 and 3 were 100 % in both the groups. Seroprotection rates for diphtheria (99.1 % vs 100 %) and polio type 2 (98.2 % vs 100 %) were observed in HEXASIIL® and comparator group, respectively. For Hepatitis B, seroprotection was >99 % in both groups. Seroconversion observed for Bordetella Pertussis (94.5 % vs 95.4 %) and Pertussis Toxin (77.1 % vs 87.2 %) in HEXASIIL® and comparator group, respectively. HEXASIIL® vaccine was found to be safe and immunogenic in toddlers and supported its further clinical development in infants. Clinical Trial Registration – CTRI/2019/11/022052. •Combination vaccines simplify vaccination schedules and improve compliance.•HEXASIIL® vaccine was compared to licensed DTwP-HepB-Hib + IPV vaccines.•HEXASIIL® had good safety and immunogenicity profile.•The data supported further evaluation of HEXASIIL® in infants.

In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Multidose human papillomavirus (HPV) vaccination is efficacious, yet the vaccine has been underused globally. Emerging data suggest that a single dose may provide protection. Whether a single dose of HPV vaccine would provide similar protection to two doses is uncertain. In this trial, we assessed whether one dose of an HPV vaccine was noninferior to two doses. Girls 12 to 16 years of age were randomly assigned, in a 1:1:1:1 ratio, to receive one or two doses of a bivalent HPV vaccine or one or two doses of a nonavalent HPV vaccine. The primary end point was new HPV type 16 or 18 infection occurring from month 12 to month 60 and persisting for at least 6 months. The prespecified noninferiority margin was 1.25 infections per 100 participants. We also assessed vaccine effectiveness by comparing HPV16 or HPV18 infection among the trial participants with that among girls and women enrolled in a nonrandomized survey. A total of 20,330 participants were enrolled and underwent randomization, and 3005 unvaccinated participants were enrolled in the survey. The noninferiority analysis showed that one vaccine dose was noninferior to two doses in preventing HPV16 or HPV18 infection. The rate difference between one and two doses of the bivalent vaccine was -0.13 infections per 100 participants (95% confidence interval [CI], -0.45 to 0.15; P<0.001 for noninferiority), and the difference between one and two doses of the nonavalent vaccine was 0.21 infections per 100 participants (95% CI, -0.09 to 0.51; P<0.001 for noninferiority). The vaccine effectiveness was at least 97% in each of the four trial groups. No safety concerns were identified. One dose of either a bivalent or nonavalent HPV vaccine provided protection against HPV16 or HPV18 infection and was not inferior to two doses. (Funded by the National Cancer Institute and others; ESCUDDO ClinicalTrials.gov number, NCT03180034.).

The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector. Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls. No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected. The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types. NCT01883609.