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Understanding persistence of humoral immune responses elicited by vaccination against coronavirus disease 2019 (COVID-19) is critical for informing the duration of protection and appropriate booster timing. We developed a mechanistic model to characterize the time course of humoral immune responses in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative adults after primary vaccination with the Janssen COVID-19 vaccine, Ad26.COV2.S. The persistence of antibody responses was quantified through mechanistic modeling-based simulations. Two biomarkers of humoral immune responses were examined: SARS-CoV-2 neutralizing antibodies determined by wild-type virus neutralization assay (wtVNA) and spike protein-binding antibodies determined by indirect spike protein enzyme-linked immunosorbent assay (S-ELISA). The persistence of antibody responses was defined as the period of time during which wtVNA and S-ELISA titers remained above the lower limit of quantification. A total of 442 wtVNA and 1,185 S-ELISA titers from 82 and 220 participants, respectively, were analyzed following administration of a single dose of Ad26.COV2.S (5 × 10

Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

Background Nasopharyngeal carriage (NPC) of Streptococcus pneumoniae is a precondition for pneumococcal disease and a source of transmission. This trial evaluated NPC of S. pneumoniae and other pathogens post-vaccination with the pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) South African children. Methods In this phase III, open, single‐centre, controlled study (ClinicalTrials.gov: NCT00829010), 484 children were stratified by HIV status: 83 HIV+, 101 HEU, and 300 HUU. HIV+ and HEU children received a 3 + 1 PHiD-CV vaccination schedule: primary vaccination, age 6/10/14 weeks, and booster dose, age 9–10 months. HUU infants were randomised (1:1:1) to 3-dose priming and booster (HUU/3+1); 3-dose priming without booster (HUU/3+0); or 2-dose priming and booster (HUU/2+1). Bacterial NPC was assessed 8 times up to 24–27 months of age. Results Overall pneumococcal carriage rates were similar across 3+1 groups irrespective of HIV status; trends towards higher carriage rates in the HIV+ than HEU and HUU/3+1 groups were observed at 24–27 months of age. In HUU children, carriage of any pneumococcal serotype was similar for the three different dosing schedules at all timepoints; carriage of vaccine-type pneumococci tended to be lower at 16–19 months and 24–27 months of age in children who had received a booster dose (HUU/2+1 and HUU/3+1 groups) than in the HUU/3+0 group. Carriage rates of NTHi, Staphylococcus aureus and Moraxella catarrhalis were comparable between all groups. Conclusions HIV infection or exposure did not seem to alter the effect of PHiD-CV on pneumococcal NPC in children during their first 2 years of life. NPC prevalence of vaccine-type pneumococci following vaccination series tended to be lower in children who had received a booster dose in comparison to those who had not.

The Ad26.COV2.S vaccine was highly effective against severe-critical coronavirus disease 2019 (Covid-19), hospitalization, and death in the primary phase 3 efficacy analysis.We conducted the final analysis in the double-blind phase of our multinational, randomized, placebo-controlled trial, in which adults were assigned in a 1:1 ratio to receive single-dose Ad26.COV2.S (5×10Median follow-up in this analysis was 4 months; 8940 participants had at least 6 months of follow-up. In the per-protocol population (39,185 participants), vaccine efficacy against moderate to severe-critical Covid-19 at least 14 days after administration was 56.3% (95% confidence interval [CI], 51.3 to 60.8; 484 cases in the vaccine group vs. 1067 in the placebo group); at least 28 days after administration, vaccine efficacy was 52.9% (95% CI, 47.1 to 58.1; 433 cases in the vaccine group vs. 883 in the placebo group). Efficacy in the United States, primarily against the reference strain (B.1.D614G) and the B.1.1.7 (alpha) variant, was 69.7% (95% CI, 60.7 to 76.9); efficacy was reduced elsewhere against the P.1 (gamma), C.37 (lambda), and B.1.621 (mu) variants. Efficacy was 74.6% (95% CI, 64.7 to 82.1) against severe-critical Covid-19 (with only 4 severe-critical cases caused by the B.1.617.2 [delta] variant), 75.6% (95% CI, 54.3 to 88.0) against Covid-19 leading to medical intervention (including hospitalization), and 82.8% (95% CI, 40.5 to 96.8) against Covid-19-related death, with protection lasting 6 months or longer. Efficacy against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was 41.7% (95% CI, 36.3 to 46.7). Ad26.COV2.S was associated with mainly mild-to-moderate adverse events, and no new safety concerns were identified.A single dose of Ad26.COV2.S provided 52.9% protection against moderate to severe-critical Covid-19. Protection varied according to variant; higher protection was observed against severe Covid-19, medical intervention, and death than against other end points and lasted for 6 months or longer. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

Ad26.COV2.S is a well-tolerated and effective vaccine against COVID-19. We evaluated durability of anti-SARS-CoV-2 antibodies elicited by single-dose Ad26.COV2.S and the impact of boosting.In randomized, double-blind, placebo-controlled, phase 1/2a and phase 2 trials, participants received single-dose Ad26.COV2.S (5 × 10Data were analyzed from phase 1/2a participants enrolled from 22 July-18 December 2020 (Cohort 1a, 18-55 years [y], N = 25; Cohort 2a, 18-55y, N = 17; Cohort 3, ≥65y, N = 22), and phase 2 participants from 14 to 22 September 2020 (18-55y and ≥ 65y, N = 73). Single-dose Ad26.COV2.S elicited stable neutralizing antibodies for at least 8-9 months and stable binding antibodies for at least 6 months, irrespective of age. A 5 × 10Single-dose Ad26.COV2.S elicited durable antibody responses for at least 8 months and elicited immune memory. Booster-elicited binding and neutralizing antibody responses were rapid and robust, even with a quarter vaccine dose, and stronger with a longer interval since primary vaccination.ClinicalTrials.gov Identifier: NCT04436276, NCT04535453.

Background: We evaluated bacterial nasopharyngeal carriage (NPC) prevalence and cumulative acquisition following 7-valent pneumococcal conjugate vaccine (PCV7) or pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administration. Methods: Participants were children from two clinical trials in a South African center who received PCV7 (n = 250) or PHiD-CV (n = 100) at ~6 weeks, ~14 weeks, and ~9–10 months of age, and were enrolled between Dec2009-Apr2010 and Mar2009-May2010 in the PCV7 and PHiD-CV studies, respectively. Sample collection, most microbiological assessments, and data re-analysis methods were identical. Results: NPC prevalence of any pneumococcal serotype was 18.5% and 17.0% at pre-vaccination, and 63.1% and 67.3% in 24–27 month-old children among PCV7 and PHiD-CV recipients, respectively. In 24–27 month-old children, 96.1% and 99.0% of PCV7 and PHiD-CV recipients had acquired ≥1 pneumococcal serotype, 53.7% and 62.9% ≥1 PCV7 serotype, 1.5%, and 3.1% ≥1 of serotypes 1, 5 or 7F, 23.2% and 19.6% serotype 6A, 23.2% and 21.7% serotype 19A, 88.7%, and 91.0% H. influenzae, and 50.3% and 62.9% Staphylococcus aureus, respectively. Conclusions: This analysis of two concurrent clinical trials did not reveal differences in bacterial NPC prevalence or acquisition in PCV7- and PHiD-CV-vaccinated children. Trial registration: South African National Clinical Trial Register (NHREC DOH-27-0511-299); ClinicalTrials.gov (NCT00829010).

BACKGROUND Pneumococcal conjugate vaccines have potential to prevent significant proportion of childhood pneumonia. Finnish Invasive Pneumococcal disease vaccine trial was designed to assess the vaccine effectiveness (VE) of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against several outcomes. We now report results for pneumonia. METHODS In this nationwide, cluster-randomised, double-blind trial, children younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants younger than 7 months at the first vaccination received either 3+1 or 2+1 vaccination schedule, children aged 7-11 months received 2+1, and those 12-18 months of age two-dose schedule. All hospitalizations and outpatient visits to hospital associated with ICD-10 codes compatible with pneumonia were identified through the National Care Register and 1-3 frontal chest X-ray images per event were collected. External readers who were unaware of the patients' vaccination status retrospectively interpreted the images. The evaluated outcomes were hospital-diagnosed, hospital-treated pneumonia as primary diagnosis, and radiologically confirmed pneumonia during the blinded, intention-to-treat follow-up period from the first vaccination to the end of 2011. Total VE was calculated as 1 minus rate ratio of all pneumonia episodes. RESULTS 47 366 children were enrolled from February 2009, to October 2010. VE against all episodes of hospital-diagnosed pneumonia was 27% (95% confidence interval [CI]: 14%, 38%), 32% (95% CI: 3%, 52%), and 23% (95% CI: -5%, 44%) in subjects enrolled at age

To support vaccination programs in developing countries, a 4-dose vial presentation of pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was developed. This study assessed immunologic non-inferiority and safety of the investigational PHiD-CV 4-dose versus licensed 1-dose vial presentation in infants.In this phase III, mono-center, observer-blind study in Bangladesh, 6-10-week-old infants were randomized 1:1 to receive PHiD-CV primary vaccination (at ages 6, 10, 18 weeks) and a booster dose (at age 9 months) with a 4-dose vial (with preservative, 4DV group) or 1-dose vial (preservative-free, 1DV group). DTPw-HBV/Hib was (co)-administered per study protocol and polio, measles and rubella vaccines as part of the national immunization program. Non-inferiority of PHiD-CV 4-dose versus 1-dose vial for each vaccine pneumococcal serotype (VT) and vaccine-related serotype 19A in terms of antibody geometric mean concentration (GMC) was assessed (criterion: upper limit of 2-sided 95% confidence interval of antibody GMC ratios [1DV/4DV]2-fold). Immune responses were measured. Solicited, unsolicited and serious adverse events (AEs) were evaluated.Of 320 infants (160 per group) vaccinated during the primary vaccination phase, 297 received a booster. Non-inferiority was demonstrated for each VT and 19A. One month post-primary vaccination, for most VT, ≥97.9% of infants in each group had antibody concentrations ≥0.2 μg/mL; for 19A ≥ 80.1% reached this threshold. Pneumococcal antibody responses and opsonophagocytic activity for each VT and 19A were within similar ranges between groups after primary and booster vaccination, as were anti-protein D responses. Booster immune responses were observed in both groups. Reported AEs were within similar ranges for both presentations.Immunologic non-inferiority of PHiD-CV 4-dose vial (with preservative) versus PHiD-CV 1-dose vial (preservative-free) was demonstrated. Immune responses and reactogenicity following primary/booster vaccination were within similar ranges for both presentations. PHiD-CV 4-dose vial would help improve access and coverage in resource-limited countries. Clinical Trial Registry: NCT02447432.

Protein D-containing vaccines may decrease acute otitis media (AOM) burden and nasopharyngeal carriage of non-typeable Haemophilus influenzae (NTHi). Protein D-containing pneumococcal conjugate vaccine PHiD-CV (Synflorix, GSK Vaccines) elicits robust immune responses against protein D. However, the phase III Clinical Otitis Media and PneumoniA Study (COMPAS), assessing PHiD-CV efficacy against various pneumococcal diseases, was not powered to demonstrate efficacy against NTHi; only trends of protective efficacy against NTHi AOM in children were shown. Areas covered: This review aims to consider all evidence available to date from pre-clinical and clinical phase III studies together with further evidence emerging from post-marketing studies since PHiD-CV has been introduced into routine clinical practice worldwide, to better describe the clinical utility of protein D in preventing AOM due to NTHi and its impact on NTHi nasopharyngeal carriage. Expert commentary: Protein D is an effective carrier protein in conjugate vaccines and evidence gathered from pre-clinical, clinical and observational studies suggest that it also elicits immune response that can help to reduce the burden of AOM due to NTHi. There remains a need to develop improved vaccines for prevention of NTHi disease, which could be achieved by combining protein D with other antigens.

Limited clinical data exists to assess differences between various infant pneumococcal conjugate vaccine schedules. In this trial, we evaluated immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered using 3 different immunization schedules in HIV unexposed-uninfected infants in South Africa.In this phase III, open, single-center, controlled study (clinicaltrials.gov: NCT00829010), 300 infants were randomized (1:1:1) to 1 of 3 PHiD-CV schedules: 3-dose priming and booster (3 + 1); 3-dose priming without booster (3 + 0); or 2-dose priming and booster (2 + 1). The booster was administered at 9-10 months of age. immune responses were assessed up to 21 months after primary vaccination.Post-priming antibody levels tended to be lower in the 2 + 1 group. At 6 months post-priming, antibody concentrations and opsonophagocytic activity titers were within similar ranges after 2- or 3-dose priming. Robust increases were observed pre- to post-booster in the 3 + 1 and 2 + 1 groups.PHiD-CV was immunogenic when administered in different schedules. Post-booster responses suggest effective immunological priming with both 2- and 3-dose primary series and support administration of the booster dose at 9-10 months of age.

We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15–18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children

Background RSV is a common cause of respiratory acute illness in older adults (OA). We evaluated safety and reactogenicity of RSVPreF3 candidate vaccine in young adults (YA) and OA. Methods In this phase I/II, placebo-controlled, multi-country trial (NCT03814590), YA aged 18–40 years were randomized 1:1:1:1 and received 2 doses of Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted vaccine, or placebo, 2 months apart. Following favorable safety evaluation, a staggered enrolment with 2 steps followed in OA aged 60–80 years, who were randomized 1:1:1:1:1:1:1:1:1:1 to receive 1 of the 9 RSV vaccine formulations containing Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo (same schedule). Safety/reactogenicity up to 1 month post-dose 1 are reported here. Results Exposed set was comprised of 48 YA and 1005 OA. Within 7 days post-dose 1, any solicited/unsolicited adverse event (AE) ranged from 58.3% to 83.3% across YA vaccinees (placebo YA: 58.3%) and from 29.9% to 84.2% across OA vaccinees (placebo OA: 33.7%) (Fig 1). Pain was the most common solicited local AE, being reported in ≤ 58.3% of YA (placebo YA: 0.0%) and at higher rates in the adjuvanted groups (≤ 75.7%) vs non-adjuvanted groups of OA (≤ 14.1%) and placebo OA (4.1%) (Fig 2A). Of solicited general AEs, fatigue (YA: ≤ 41.7% in vaccinees vs 50.0% in placebo; OA: ≤ 48.5% in vaccinees vs 16.3% in placebo) and headache (YA: ≤ 33.3% in vaccinees vs 16.7% in placebo; OA: ≤ 27.7% in vaccinees vs 8.2% in placebo) were most commonly reported (Fig 2B), while fever ≥ 38.0 °C was observed in ≤ 3.0% of OA vaccinees (placebo OA: 0.0%). Grade 3 solicited local and general AEs were observed in OA only, with erythema (≤ 4.9% in vaccinees vs 0.0% in placebo) and fatigue (≤ 2.0% in vaccinees vs 1.0% in placebo) being most common (Fig 2). No serious AEs (SAEs) were reported in YA. A number of 11 OA reported a SAE within 1 month post-dose 1, but none was fatal or assessed as vaccine-related. No clinically significant abnormalities occurred in hematological/biochemical parameters in any group. Figure 1. Percentage of participants presenting at least one type of solicited/unsolicited adverse event (AE) within 7 days post-dose 1 Figure 2. Percentage of participants with at least one type of solicited adverse event (AE) within 7 days post-dose 1 Conclusion First dose of RSVPreF3 candidate vaccine is well tolerated. AE rates tended to be higher after AS01B-adjuvanted formulations compared to other vaccine formulations. No safety concerns were raised. Funding GlaxoSmithKline Biologicals SA Disclosures Jelena Tica, PhD, GSK group of companies (Employee, Shareholder) Javier Ruiz Guiñazú, MD MSc, GSK group of companies (Employee, Shareholder) Charles P. Andrews, MD, GSK group of companies (Scientific Research Study Investigator) Charles Fogarty, MD, GSK group of companies (Grant/Research Support) Edward Kerwin, MD, Amphastar (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)AstraZeneca (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Boehringer Ingelheim (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Chiesi (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Cipla (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)GSK group of companies (Employee, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Mylan (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Novartis (Employee, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)other around 40 pharmaceutical companies (Other Financial or Material Support, conducted multicenter clinical research trials)Pearl (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Sunovion (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Theravance (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Isabel Leroux-Roels, MD PhD, GSK group of companies (Scientific Research Study Investigator) Corinne Vandermeulen, MD PhD, GSK group of companies (Other Financial or Material Support, My university only received Grant/Research Support) Marie-Pierre David, MSc, GSK group of companies (Employee, Shareholder) Nancy Dezutter, PhD, PharmD, RPh, GSK group of companies (Employee, Shareholder) Laurence Fissette, MSc, GSK group of companies (Employee) Juliane Koch, MD, GSK group of companies (Employee, Shareholder) Narcisa Mesaros, MD, MSc, GSK group of companies (Employee)

This phase III, randomized, open-label, multicenter study (NCT01027845) conducted in Japan assessed the immunogenicity, safety, and reactogenicity of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, given intramuscularly) co-administered with diphtheria-tetanus-acellular pertussis vaccine (DTPa, given subcutaneously). Infants (N=360 ) were randomized (2:1) to receive either PHiD-CV and DTPa (PHiD-CV group) or DTPa alone (control group) as 3-dose primary vaccination (3-4-5 months of age) and booster vaccination (17-19 months of age). Immune responses were measured before and one month after primary/booster vaccination and adverse events (AEs) were recorded. Post-primary immune responses were non-inferior to those in pivotal/efficacy European or Latin American pneumococcal protein D-conjugate vaccine studies. For each PHiD-CV serotype, at least 92.6% of infants post-primary vaccination and at least 97.7% of children post-booster had pneumococcal antibody concentrations ≥0.2 μg/ml, and at least 95.4% post-primary and at least 98.1% post-booster had opsonophagocytic activity (OPA) titers ≥8 . Geometric mean antibody concentrations and OPA titers (except OPA titer for 6B) were higher post-booster than post-priming for each serotype. All PHiD-CV-vaccinated children had anti-protein D antibody concentrations ≥100 EL.U/ml one month post-primary/booster vaccination and all were seroprotected/seropositive against each DTPa antigen. Redness and irritability were the most common solicited AEs in both groups. Incidences of unsolicited AEs were comparable between groups. Serious AEs were reported for 47 children (28 in PHiD-CV group); none were assessed as vaccine-related. In conclusion, PHiD-CV induced robust immune responses and was well tolerated when co-administered with DTPa in a 3-dose priming plus booster regimen to Japanese children.

Supplemental Digital Content is available in the text, Background: Phase III, open-label, single-center, controlled study in South Africa (ClinicalTrials.gov: NCT00829010) to evaluate immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) children. Methods: Children stratified by HIV status received PHiD-CV primary vaccination (age 6/10/14 weeks; coadministered with routine childhood vaccines) and booster dose (age 9–10 months). Immune responses, assessed using enzyme-linked immunosorbent and functional assays, and safety were evaluated up to 14 months post-booster. Results: Of 83, 101, and 100 children enrolled in HIV+, HEU, and HUU groups, 70, 91, and 93 were included in according-to-protocol immunogenicity cohort. For each vaccine-serotype, percentages of children with antibody concentrations ≥0.2 μg/mL were ≥97% 1 month post-primary vaccination and ≥98.5% 1 month post-booster (except for 6B and 23F at both timepoints). Post-primary vaccination, functional antibody responses were lower in HIV+ children: for each vaccine-serotype, percentages of children with opsonophagocytic activity (OPA) titres ≥8 were ≥72%, ≥81%, and ≥79% for HIV+, HEU, and HUU children. Post-booster, ≥87% of children in each group had OPA titres ≥8. Reactogenicity was similar across groups. Thirty one (37%) HIV+, 25 (25%) HEU, and 20 (20%) HUU children reported ≥1 serious adverse event. Five HIV+ and 4 HEU children died. One death (sudden infant death syndrome; HEU group; 3 days post-dose 1) was considered potentially vaccine-related. Conclusion: PHiD-CV was immunogenic and well-tolerated in HIV+, HEU, and HUU children, and has the potential to provide substantial benefit irrespective of HIV infection status.

This randomized single-blind study in Korea evaluated noninferiority of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) versus the 7-valent pneumococcal conjugate vaccine (7vCRM) when both were coadministered with H. influenzae type b (Hib) conjugate vaccine, as opposed to coadministration with diphtheria-tetanus-acellular pertussis-based combination vaccines in previous studies.Infants received 3 primary doses at 2, 4, and 6 months and a booster dose at 12 to 18 months of PHiD-CV (N = 374) or 7vCRM (N = 129), both coadministered with Hib vaccine. Immune responses were measured 1 month postdose 3 and postbooster using 22F-inhibition enzyme-linked immunosorbent assay and functional opsonophagocytic activity assay.PHiD-CV-induced antibody responses against each of the vaccine pneumococcal serotypes and protein D. Noninferiority to 7vCRM was demonstrated for all 10 PHiD-CV serotypes in terms of percentages of subjects reaching an antibody concentration ≥0.2 μg/mL after primary vaccination. Postprimary and postbooster, percentages of subjects with antibody concentration ≥0.2 μg/mL or opsonophagocytic activity titer ≥8 were generally consistent between groups for each pneumococcal serotype common to both vaccines. The safety and reactogenicity profiles of PHiD-CV and 7vCRM were generally comparable after both primary and booster vaccination.In this Korean study, 3-dose PHiD-CV priming followed by a booster dose was immunogenic for all 10 vaccine pneumococcal serotypes and protein D. Noninferiority to 7vCRM in terms of enzyme-linked immunosorbent assay threshold responses postpriming was demonstrated. The safety and reactogenicity profiles of both vaccines when coadministered with Hib vaccine were generally comparable.