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Introduction: The use of novel adjuvants in human vaccines continues to expand as their contribution to preventing disease in challenging populations and caused by complex pathogens is increasingly understood. AS01 is a family of liposome-based vaccine Adjuvant Systems containing two immunostimulants: 3- O -desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01-containing vaccines have been approved and administered to millions of individuals worldwide., Areas Covered: Here, we report advances in our understanding of the mode of action of AS01 that contributed to the development of efficacious vaccines preventing disease due to malaria, herpes zoster, and respiratory syncytial virus. AS01 induces early innate immune activation that induces T cell-mediated and antibody-mediated responses with optimized functional characteristics and induction of immune memory. AS01-containing vaccines appear relatively impervious to baseline immune status translating into high efficacy across populations. Currently licensed AS01-containing vaccines have shown acceptable safety profiles in clinical trials and post-marketing settings., Expert Opinion: Initial expectations that adjuvantation with AS01 could support effective vaccine responses and contribute to disease control have been realized. Investigation of the utility of AS01 in vaccines to prevent other challenging diseases, such as tuberculosis, is ongoing, together with efforts to fully define its mechanisms of action in different vaccine settings.

Background: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. This study aimed to describe the clinical efficacy and safety of a bivalent SARS-CoV-2 recombinant protein vaccine as a two-injection primary series during a period of circulation of the omicron (B.1.1.529) variant., Methods: We conducted a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial in adults aged 18 years or older at 54 clinical research centres in eight countries (Colombia, Ghana, India, Kenya, Mexico, Nepal, Uganda, and Ukraine). Participants were recruited from the community and randomly assigned (1:1) by use of an interactive response technology system to receive two intramuscular 0·5 mL injections, 21 days apart, of the bivalent vaccine (5 μg of ancestral [D614] and 5 μg of beta [B.1.351] variant spike protein, with AS03 adjuvant) or placebo (0·9% normal saline). All participants, outcome assessors, and laboratory staff performing assays were masked to group assignments; those involved in the preparation and administration of the vaccines were unmasked. Participants were stratified by age (18-59 years and ≥60 years) and baseline SARS-CoV-2 rapid serodiagnostic test positivity. Symptomatic COVID-19 was defined as laboratory-confirmed (via nucleic acid amplification test or PCR test) COVID-19 with COVID-19-like illness symptoms. The primary efficacy endpoint was the clinical efficacy of the bivalent vaccine for prevention of symptomatic COVID-19 at least 14 days after the second injection (dose 2). Safety was assessed in all participants receiving at least one injection of the study vaccine or placebo. This trial is registered with ClinicalTrials.gov (NCT04904549) and is closed to recruitment., Findings: Between Oct 19, 2021, and Feb 15, 2022, 13 002 participants were enrolled and randomly assigned to receive the first dose of the study vaccine (n=6512) or placebo (n=6490). 12 924 participants (6472 in the vaccine group and 6452 in the placebo group) received at least one study injection, of whom 7542 (58·4%) were male and 9693 (75·0%) were SARS-CoV-2 non-naive. Of these 12 924 participants, 11 543 (89·3%) received both study injections (5788 in the vaccine group and 5755 in the placebo group). The efficacy-evaluable population after dose 2 comprised 11 416 participants (5736 in the vaccine group and 5680 in the placebo group). The median duration of follow-up was 85 days (IQR 50-95) after dose 1 and 58 days (29-70) after dose 2. 121 symptomatic COVID-19 cases were reported at least 14 days after dose 2 (32 in the vaccine group and 89 in the placebo group), with an overall vaccine efficacy of 64·7% (95% CI 46·6 to 77·2). Vaccine efficacy against symptomatic COVID-19 was 75·1% (95% CI 56·3 to 86·6) in SARS-CoV-2 non-naive participants and 30·9% (-39·3 to 66·7) in SARS-CoV-2-naive participants. Viral genome sequencing identified the infecting strain in 68 (56·2%) of 121 cases (omicron [BA.1 and BA.2] in 63; delta in four; and both omicron and delta in one). Immediate unsolicited adverse events were reported by four (<0·1%) participants in the vaccine group and seven (0·1%) participants in the placebo group. Immediate unsolicited adverse reactions within 30 min after any injection were reported by four (<0·1%) participants in the vaccine group and six (<0·1%) participants in the placebo group. In the reactogenicity subset with available data, solicited reactions (solicited injection-site reactions and solicited systemic reactions) within 7 days after any injection occurred in 1398 (57·8%) of 2420 vaccine recipients and 983 (40·9%) of 2403 placebo recipients. Grade 3 solicited reactions were reported by 196 (8·1%; 95% CI 7·0 to 9·3) of 2420 vaccine recipients and 118 (4·9%; 4·1 to 5·9) of 2403 placebo recipients within 7 days after any injection, with comparable frequencies after dose 1 and dose 2 in the vaccine group. At least one serious adverse event occurred in 30 (0·5%) participants in the vaccine group and 26 (0·4%) in the placebo group. The proportion of adverse events of special interest and deaths was less than 0·1% in both study groups. No adverse event of special interest, serious adverse event, or death was deemed to be treatment related. There were no reported cases of thrombosis with thrombocytopenia syndrome, myocarditis, pericarditis, Bell's Palsy, or Guillain-Barré syndrome, or other immune-mediated diseases., Interpretation: The bivalent variant vaccine conferred heterologous protection against symptomatic SARS-CoV-2 infection in the epidemiological context of the circulating contemporary omicron variant. These findings suggest that vaccines developed with an antigen from a non-predominant strain could confer cross-protection against newly emergent SARS-CoV-2 variants, although further investigation is warranted., Funding: Sanofi, US Biomedical Advanced Research and Development Authority, and the US National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests GHD, MIB, BF, M-HG, MC, JA, CAD, RMC, SG, SSr, and SSa are Sanofi employees. MIB, BF, M-HG, JA, CAD, RMC, and SSr hold stock or stock options in Sanofi. SG, RMC, and SSr hold patents pending on a COVID-19 vaccine. The Center for Vaccine Development and Global Health (CVD) receives grants from Pfizer to conduct clinical trials of COVID-19 vaccines. KMN receives no salary support for this grant. KMN receives grants from the US National Institutes of Health (NIH) to participate in overall organisation of COVID-19 vaccine trials and for participation in vaccine trials. RMC has received institutional funding from the Biomedical Advanced Research and Development Authority (BARDA) for the present study; has received support for attending meetings or travel, from Sanofi; and holds patents planned, issued, or pending from Sanofi. M-HG has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Sanofi. NR has received institutional funding from the NIH; and institutional grants or contracts from Merck, Sanofi, Quidel, Pfizer, and Lilly. SRW has received institutional funding from Sanofi and the National Institute of Allergy and Infectious Diseases (NIAID) and NIH; and institutional grants or contracts from Janssen Vaccines/Johnson & Johnson, Moderna Tx, Vir Biotechnology, and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson; and his spouse holds stocks and stock options in Regeneron Pharmaceuticals. NG has received institutional funding from Sanofi, GSK, and the NIAID and NIH; and is in receipt of grants or contracts from the NIH, NIAID, and the Division of AIDS (DAIDS). MA and TT are employees of NIAID, which funded aspects of the current study. LS, MAC, and MK are employees of GSK and own shares in the GSK group of companies. MJ and JJK have received institutional support from Sanofi and NIAID and NIH with respect to this study. MLR has received institutional support or contracts for the present manuscript from Walter Reed Army Institute of Research, Ingenuity Pathway Analysis, and the US Medical Research and Development Command. SSa was a Sanofi employee at the time of study conduct; and holds patents planned, issued, or pending on COVID-19 vaccines. LC has received grant funding from the NIAID/NIH. AC, KPA, ASB, TB, DD, MK-J, HK, RM, NLM, HR, SMVM, FS, JT, and TAW, declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The literature on first generation COVID-19 vaccines show they were less effective against new SARS-CoV-2 variants of concern including Omicron (BA.1, BA.2, BA.4 and BA.5 subvariants). New vaccines developed against variant strains may provide cross-protection against emerging variants when used as boosters and facilitate vaccination across a range of countries, healthcare settings and populations. However, there are no data on such vaccines when used as a primary series., Methods: A global Phase 3, multi-stage efficacy study (NCT04904549) among adults (≥18 years) was conducted in 53 research centres in eight countries (United States, Honduras, Japan, Colombia, Kenya, India, Ghana, Nepal). Participants were randomized 1:1 to receive two intramuscular injections of a monovalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (10 μg of the spike (S) protein from the ancestral D614 strain) or placebo on Day 1 (D01) and Day 22 (D22). The primary efficacy endpoint was prevention of virologically confirmed SARS-CoV-2 infection with symptoms of COVID-19-like illness (CLI) ≥14 days after the second injection (post-dose 2 [PD2]) in participants who were SARS-CoV-2 naïve on D01 + D22. Safety and reactogenicity were also evaluated., Findings: Between May 26 and November 7, 2021, 10,114 participants received ≥1 study injection, and 9441 participants received both injections. 2108 (20.8%) participants were SARS-CoV-2 naïve at D01 and D22. The primary endpoint was analysed in a subset of the full analysis set (the modified full analysis set PD2 [mFAS-PD2], excluding participants who did not complete the vaccination schedule or received vaccination despite meeting one of the contraindication criteria, had onset of symptomatic COVID-19 between the first injection and before 14 days after the second injection, or participants who discontinued before 14 days after the second injection [n = 9377; vaccine, n = 4702; placebo, n = 4675]). Data were available for 2051 SARS-CoV-2 naïve and 7159 non-naïve participants. At the cut-off date (January 28, 2022), symptomatic COVID-19 was reported in 169 naïve participants (vaccine, n = 81; placebo, n = 88) ≥14 days PD2, with a vaccine efficacy (VE) of 15.3% (95% CI, -15.8; 38.2). VE regardless of D01/D22 serostatus was 32.9% (95% CI, 15.3; 47.0) and VE in non-naïve participants was 52.7% (95% CI, 31.2; 67.9). Viral genome sequencing was performed up to the data cut-off point and identified the infecting strain in 99/169 adjudicated cases in the PD2 naïve population (Delta [25], Omicron [72], other variants [3], one participant had infection with both Delta and Omicron variants and has been included in the totals for both Delta and Omicron). The vaccine was well-tolerated with an acceptable safety profile., Interpretation: In the context of changing circulating viral variants, it is challenging to induce protection in naïve individuals with a two-dose priming schedule based on the parental D614 strain. However, while the primary endpoint of this trial was not met, the results show that a monovalent D614 vaccine can still be of value in individuals previously exposed to SARS-CoV-2., Funding: This study was funded in whole or in part by Sanofi and by federal funds from the Biomedical Advanced Research and Development Authority, part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under contract number HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense under contract number W15QKN-16-9-1002. The views presented here are those of the authors and do not purport to represent those of the Department of the Army, the Department of Health and Human Services, or the U.S. government., Competing Interests: GHD, JA, MIB, MC, M-HG, JA, CAD, RMC, MC and SSa are Sanofi employees. JA, MIB, M-HG, JA, CAD, RMC, MC, CAD, SSr and SSa hold stock or stock options in Sanofi. SSr and SSa are the named inventors on a patent associated with the vaccine reported in this manuscript. RMC has received institutional funding from BARDA for the present study; has received support for attending meetings and/or travel from Sanofi; and holds patents planned, issued or pending from Sanofi. NR has received institutional funding from the National Institutes of Health; and institutional grants or contracts from Merck, Sanofi, Quidel, Pfizer and Lilly. SRW has received institutional funding from Sanofi and the National Institute of Allergy and Infectious Diseases/National Institutes of Health; and institutional grants or contracts from Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. NG has received institutional grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID). LS, MAC and MK are employees of the GSK group of companies and own shares in the GSK group of companies. MJ and JJK have received institutional support from Sanofi and the NIAID/NIH with respect to this study. MLR has received institutional support/contracts for the present manuscript from WRAIR IPA and the US Medical Research and Development Command. MA, and MKJ are employees of the NIAID, which funded aspects of the current study; The NIAID provides grant funding to the HIV Vaccine Trials Network (HVTN) Leadership and Operations Center (UM1 AI 68614HVTN), the Statistics and Data Management Center (UM1 AI 68635), the HVTN Laboratory Center (UM1 AI 68618), the HIV Prevention Trials Network Leadership and Operations Center (UM1 AI 68619), the AIDS Clinical Trials Group Leadership and Operations Center (UM1 AI 68636), and the Infectious Diseases Clinical Research Consortium leadership group 5 (UM1 AI 148684-03). One of the sites in Kenya in this study received funding from NIAID. LC has received grant funding from the NIAD/NIH. The Center for Vaccine Development and Global Health (CVD) receives grants from Pfizer to conduct clinical trials of COVID-19 vaccines: KMN receives no salary support for this grant. KMN receives grants from NIH to participate in overall organization of COVID vaccine trials and for participation in vaccine trials. ASB has received honorarium for the conduct of this trial as Principal Investigator from Sanofi Healthcare India Private Limited. TT, SK, BF, AC, KPA, TB, RM, NLM, HR, FS, JT, SG, KS, AU and RS have no interests to declare., (© 2023 The Author(s).)

Background: In a parallel-group, international, phase 3 study (ClinicalTrials.govNCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03)., Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18-55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18-55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18-55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety., Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18-55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58-29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71-46.95) (anti-B.1.351); and for BiV, 14.39 (11.39-18.28) (anti-D614G) and 34.18 (25.84-45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified., Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine., Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA)., Competing Interests: GdB, JW, AP, MSR, HA, MIB, RMCa, RF, BF, JG, M-HG, SG, OH, RM, JP, NR, RMCh and SSr are Sanofi employees. GdB, AP, MIB, BF, OH, NR, RMCh and SSr hold stock or stock options in Sanofi. SSa was a Sanofi employee at the time of study conduct and held shares and/or stock options in the company at the time of study conduct. GdB, SSr, RMCh, and SSa are inventors on a pending patent application filed by Sanofi and GSK for the development of the CoV-2 dTM vaccine. MAC, LS and MK are employed by GSK and hold restricted shares in the GSK group of companies. FTDS was employed by GSK and held restricted shares in the GSK group of companies, at the time of the study. FMT declares trial fees paid to their institution by Sanofi; honoraria received from GSK group of companies, Pfizer Inc., Sanofi, MSD, Moderna, Biofabri, AstraZeneca, Novavax, Janssen; meeting and/or travel fees received from Pfizer Inc, MSD, GSK and Sanofi; data safety monitoring board or advisory board participation for Pfizer and Biofabri; being a member of ETAGE–WHO Europe, coordinator of the Spanish Pediatric Critical Trials Network and coordinator of the WHO Collaborating Centre for Vaccines Safety of Santiago de Compostela; and payments made to their institution for their role as principal investigator in randomized controlled trials for Ablynx, Abbot, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, Medimmune, Novavax, Novartis and GSK. DMRM declares that her institution received funding from Sanofi. AF receives research funding, paid to his employers, from Sanofi both for work related to this study and other unrelated vaccine trials and from GSK for other unrelated studies. He receives research funding from other vaccine manufacturers relating to trials and studies and undertakes paid consultancy related to a number of developmental antimicrobial drugs and vaccines. OL declares that their institution received funding for conducting the trial. NLM received travel support from Sanofi and chaired a Scientific Advisory Board for them, unrelated to current study. LDS received a research grant from Sanofi. SD, SA, DB, AB, DD, PG, JAH, CR and AW declare no conflicts of interest., (© 2023 The Author(s).)

Introduction: This observational retrospective matched cohort study evaluated the safety of a prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination, Boostrix. We previously reported on the risk of maternal and neonatal outcomes; here we report on the risk of congenital anomalies in infants at birth through 6 months of age., Methods: The study included pregnant Kaiser Permanente Southern California members. Women who received the Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019 were matched to women who were pregnant between January 2012 and December 2014 and were not vaccinated with Tdap during pregnancy. Unadjusted and adjusted relative risks (aRRs) with 95% confidence intervals were estimated by Poisson regression. Quantitative secular trend analyses, from 2011 to 2017, were conducted on congenital anomalies with a statistically significant aRR > 1., Results: The analysis consisted of 16,350 and 16,088 live-born infants in the Tdap-exposed and unexposed cohorts, respectively. Of the 14 congenital anomaly body systems evaluated, 8 (eye, ear/face/neck, respiratory, upper gastrointestinal, genital, renal, musculoskeletal, integument) had statistically significant elevated aRRs, with point estimates ranging from 1.17 to 2.02. The observed elevated aRRs were consistent with their respective secular increases over time., Conclusion: Cautious interpretation of these findings is warranted as these increases may have resulted from improved identification and diagnosis. Furthermore, the biological plausibility of an association between maternal vaccine exposure in the third trimester of pregnancy and birth defects is low. The overall study findings support the safety of maternal immunization with Boostrix during the third trimester of pregnancy., Trial Registration: ClinicalTrials.gov identifier, NCT03463577., (© 2022. The Author(s).)

As the SARS-CoV-2 pandemic evolves, vaccine evaluation needs to include consideration of both durability and cross-reactivity. This report expands on previously reported results from a Phase 1 trial of an AS03-adjuvanted, plant-based coronavirus-like particle (CoVLP) displaying the spike (S) glycoprotein of the ancestral SARS-CoV-2 virus in healthy adults (NCT04450004). Humoral and cellular responses against the ancestral strain were evaluated 6 months post-second dose (D201) as secondary outcomes. Independent of dose, all vaccinated individuals retain binding antibodies, and ~95% retain neutralizing antibodies (NAb). Interferon gamma and interleukin-4 responses remain detectable in ~94% and ~92% of vaccinees respectively. In post-hoc analyses, variant-specific (Alpha, Beta, Delta, Gamma and Omicron) NAb were assessed at D42 and D201. Using a live virus neutralization assay, broad cross-reactivity is detectable against all variants at D42. At D201, cross-reactive antibodies are detectable in almost all participants against Alpha, Gamma and Delta variants (94%) and the Beta variant (83%) and in a smaller proportion against Omicron (44%). Results are similar with the pseudovirion assay. These data suggest that two doses of 3.75 µg CoVLP+AS03 elicit a durable and cross-reactive response that persists for at least 6 months post-vaccination., (© 2022. The Author(s).)

The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18-64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in &gt;35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (&gt;80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (&gt;88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities., (© 2022. The Author(s).)

The objective of this study was to evaluate the safety of prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination. This cohort study was conducted among pregnant members at Kaiser Permanente Southern California (KPSC). The exposed cohort consisted of women who received Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019. The unexposed cohort consisted of matched women who were pregnant between January 2012 and December 2014 and were not vaccinated with any Tdap vaccine throughout their pregnancy. Maternal and infant characteristics and pre-specified endpoints were collected through automated data and review of the electronic health records. Unadjusted and adjusted relative risks (aRRs) with confidence intervals (CIs) were estimated by Poisson regression. Non-inferiority testing (i.e., to rule out a two-fold increase) was conducted for primary endpoints with adjustment for multiplicity. Superiority testing was conducted without multiplicity adjustment for secondary endpoints. The analysis consisted of 16,606 pairs of Tdap recipients and unexposed pregnant women. For the primary endpoints, the aRR for preeclampsia/eclampsia was 1.38 (98.75% CI:1.21-1.58) and the aRR for intrauterine infection was 1.28 (98.75% CI:1.12-1.47). These increases were consistent with the background increasing trend of these diagnoses among all pregnant women at KPSC since 2011, and the upper limit of the 98.75% CI of both aRRs did not exceed the pre-specified threshold of 2. No increased risks of small for gestational age (aRR = 1.04, 98.75% CI:0.94-1.16) or preterm delivery (aRR = 0.71, 98.75% CI:0.64-0.78) were observed. No evidence of increased risks for secondary endpoints, including poor fetal growth, preterm pre-labor rupture of membranes, stillbirth/fetal death, placental abruption, transfusion during delivery hospitalization, and neonatal death, was observed. Prenatal Tdap vaccination after the 27th week of pregnancy was not associated with increased risks of pre-specified maternal and infant outcomes, supporting the safety of Tdap vaccination during pregnancy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Hung Fu Tseng reports financial support was provided by GSK Vaccines. Hung Fu Tseng reports a relationship with Moderna Therapeutics Inc that includes: funding grants. HFT, GSL, and YT received research funding from GSK group of companies and Moderna for other studies outside of the submitted work. LSS received research funding from GSK group of companies, Novavax, Seqirus, Dynavax, and Moderna for other studies outside of the submitted work. BKA received research funding from GSK group of companies, Novavax, Seqirus, Dynavax, Moderna, Pfizer, and Genentech for other studies outside of the submitted work. YL received research funding from GSK group of companies, Seqirus, Moderna, and Pfizer for other studies outside of the submitted work. AF received research funding from GSK group of companies, Moderna, Pfizer, and Gilead for other studies outside of the submitted work. TBC received research funding from GSK group of companies for other studies outside of the submitted work. SYT received research funding from Pfizer for other studies outside of the submitted work. CT received research funding from GSK and Novavax for other studies outside of the submitted work. LC, MAC, AK, LV, BC, NMeyer and AG are employees of the GSK group of companies. LC, MAC, AK, LV, BC, NMeyer and AG hold shares in the GSK group of companies. JEP, DR and NMesaros were employees of the GSK group of companies and held shares at the time of this study. The authors have no non-financial competing interest to declare. LQ received research funding from GSK group of companies, Moderna, and Dynavax for other studies outside of the submitted work.]., (Copyright © 2022 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Background: Vaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles, displaying the receptor-binding domain (RBD) in a highly immunogenic array., Methods: This randomised, placebo-controlled, observer-blinded phase 1/2 study was conducted to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19-85 years at 14 hospital sites in Korea. This study was consisted of two stages (stage I, healthy adults aged 19-55 years; stage II, 240 healthy adults aged 19-85 years). Healthy participants who did not previously receive any vaccine within 4 weeks (2 weeks for flu vaccine) prior to the study, no history of COVID-19 vaccination/medication, and were naïve to SARS-CoV-2 infection at screening were eligible for the study enrollment. Participants were block-randomized in a 2:2:1 ratio to receive 2 doses of 10 µg GBP510 adjuvanted with AS03 (group 1), 10 µg unadjuvanted GBP510 (group 2) or placebo intramuscularly in stage I, while they were block-randomized in a 2:2:1:1 ratio to receive 10 µg GBP510 adjuvanted with AS03 (group 1), 25 µg GBP510 adjuvanted with AS03 (group 3), 25 µg unadjuvanted GBP510 (group 4) or placebo in stage II. The primary safety outcomes were solicited and unsolicited adverse events, while primary immunogenicity outcomes included anti-SARS-CoV-2 RBD IgG antibodies; neutralizing antibody responses; and T-cell immune responses. Safety assessment included all participants who received at least 1 dose of study intervention (safety set). Immunogenicity assessment included all participants who completed the vaccination schedule and had valid immunogenicity assessment results without any major protocol deviations (per-protocol set). This study was registered with ClinicalTrials.gov (NCT04750343)., Findings: Of 328 participants who were enrolled between February 1 and May 28, 2021, 327 participants received at least 1 dose of vaccine. Each received either 10 µg GBP510 adjuvanted with AS03 (Group 1, n  = 101), 10 µg unadjuvanted GBP510 (Group 2, n  = 10), 25 µg GBP510 adjuvanted with AS03 (Group 3, n  = 104), 25 µg unadjuvanted GBP510 (Group 4, n  = 51), or placebo ( n  = 61). Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. The most frequently reported solicited local adverse event (AE) was injection site pain after any vaccination: (88·1% in group 1; 50·0% in group 2; 92·3% in group 3; 66·7% in group 4). Fatigue and myalgia were two most frequently reported systemic AEs and more frequently reported in GBP510 adjuvanted with AS03 recipients (79·2% and 78·2% in group 1; 75·0% and 79·8% in group 3, respectively) than in the unadjuvanted vaccine recipients (40·0% and of 40·0% in group 2; 60·8% and 47·1% in group 4) after any vaccination. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic AEs. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163·6/2599·2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 µg/25 µg) by 14 days after the second dose. Two-dose vaccination of 10 µg or 25 µg GBP510 adjuvanted with AS03 induced high titres of neutralizing antibody via pseudovirus (1369·0/1431·5 IU/mL) and wild-type virus (949·8/861·0 IU/mL) assay., Interpretation: GBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3., Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investment ID OPP1148601. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study., Competing Interests: WSC received funding from SK Bioscience, and payment for lectures on adult immunization to Korean physicians. MA, FS, FR, and AP are employees of the GSK group of companies. MA, FR, and AP hold restricted shares in the GSK group of companies. DV received a grant and consulting fees from Vir Biotechnology. NPK is a co-founder, shareholder, paid consultant, and chair of the scientific advisory board of Icosavax, Inc. DV and NPK received a grant of University of Washington supported by Bill & Melinda Gates Foundation. NPK also received grants of University of Washington supported by GSK and Pfizer; those were unrelated to the present manuscript. NPK received royalties from licensed technology unrelated to the present manuscript. NPK received Honoraria for lectures for Pfizer, Amgen, Washington University St. Louis, University of New Mexico, Children's Hospital Seattle and Lawrence Berkeley National Lab. NPK, ACW, and DV are named as inventors on patent applications filed by the University of Washington for SARS-CoV-2 and sarbecovirus nanoparticle vaccines. HK, JHR, SJL, YWP, and HKP are full-time employees of SK Bioscience. HK, YWP, and HKP own SK Bioscience stock as employees. HKP participated in the blinded session of data safety monitoring board as an observer (NCT04750343). All other authors declare no competing interests., (© 2022 Published by Elsevier Ltd.)

Background: Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine., Methods: In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases., Results: A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%)., Conclusions: The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial., Methods: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here., Findings: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group., Interpretation: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination., Funding: Sanofi Pasteur and Biomedical Advanced Research and Development Authority., Competing Interests: Declaration of interests SSr, MIB, A-LC, AC, RMC, BF, HJ, YM, ER, NR, DvB, GdB, RC, M-HG, DL, RM, SM, CM, CAD, and SSa are Sanofi Pasteur employees. SSr, MIB, HJ, CM, and SSa own stock or stock options; A-LC, NR, and M-HG hold shares or restricted shares; and RMC reports owning shareholder and vesting options in Sanofi Pasteur. SSr, RMC, GdB, CAD, and SSa are inventors on a pending patent application filed by Sanofi Pasteur and GlaxoSmithKline (GSK) for the development of the CoV-2 dTM vaccine. LS, MK, MAC, and FT-D-S are employed by, and hold restricted shares in, the GSK group of companies. AJ was contracted by Sanofi Pasteur. DD received funding from Sanofi Pasteur for his institution, George Washington University, to serve as a clinical site for the vaccine trial. NG reports receiving funding and study materials from Sanofi and funding from the National Institute of Allergy and Infectious Diseases (NIAID) through the COVID-19 Prevention Network (CoVPN), which provides research grants to her institution, the Fred Hutchinson Cancer Research Center. MCK received NIAID funding support for the current study, paid to the clinical trials site for the CoVPN and HIV vaccine trials network; Sanofi Pasteur contracted the site to do this clinical trial. DMRM received a research grant from Sanofi Pasteur for this study. OO received a Gilead Sciences grant paid to Yale, and consulting fees from Gilead Sciences. OO also reports that Gilead, Integrity CE, and Medscape paid for lectures, presentations, manuscript writing, or educational events and that Gilead and ViiV Healthcare paid for their participation on a data safety monitoring or advisory board. VNR received funding from Sanofi for the CoVPN and Vaccine Treatment and Evaluation Units for COVID-19 vaccine clinical trials, and payments from Pfizer to her institution for the conduct of COVID-19 vaccine clinical trials. RS received clinical trial investigator site contracts with AES Synexus. NGR received a grant from Sanofi Pasteur to do this study and received grants from Sanofi, Merck, Pfizer, Quidel, and Lilly in the past 36 months. NGR received a payment from the Infectious Disease Association of California and participated on advisory or safety monitoring boards for Micron, ICON, and The Emmes Company; NGR also reports having a leadership or fiduciary role (paid or unpaid) for the Infectious Diseases Society of America, the Vaccine Treatment and Evaluation Unit and Antibacterial Resistance Leadership Group. LDS received a research grant from Sanofi Pasteur and SRW and JW were contracted by Sanofi Pasteur. AB, BJE, NLM, SSM, MKJ, SR, JS, TT, and JT declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: GSK initiated a Pregnancy Registry in the United States (US) for the reduced-antigen-content tetanus-diphtheria-acellular pertussis (Tdap; Boostrix, GSK) vaccine with the aim to detect and describe pregnancy outcomes in women vaccinated with Boostrix 28 days before estimated conception or during pregnancy., Methods: Voluntary reports of pregnancy exposure to Boostrix received from spontaneous and post-marketing surveillance sources in the US were assessed. Reports were classified as prospective or retrospective based on the knowledge of pregnancy outcomes at the time of reporting. For completeness, reports of exposure to Boostrix or to the Tdap-inactivated poliovirus vaccine (Boostrix-IPV, GSK) reported to the global safety database from countries outside the US were also evaluated., Results: From May 2005 to August 2019, 1517 (1455 prospective and 62 retrospective) pregnancy reports were received in the Boostrix US Pregnancy Registry. Of the prospective reports, 250 had known outcomes: 244 live infants with no apparent birth defects (BDs), three live infants with BDs, and three spontaneous abortions with no apparent BDs. Of the retrospective reports, 55 had known outcomes: 33 live infants with no apparent BDs, 16 live infants with BDs, one spontaneous abortion with no apparent BDs, four stillbirths with no apparent BDs, and one stillbirth with BDs. Cumulatively, 1321 pregnancy reports (1006 for Boostrix; 315 for Boostrix-IPV) were received from countries outside the US. Of these, 163 prospective reports and 551 retrospective reports had known outcomes. Results were in line with those from the Boostrix US Pregnancy Registry., Conclusions: Data currently available from the Boostrix US Pregnancy Registry and from countries outside the US suggested that exposure to Boostrix or Boostrix-IPV during pregnancy does not raise safety concerns related to adverse pregnancy outcomes or BDs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AJ is employee of the GSK group of companies. AK, LC, MAC, and FTDS are employees of the GSK group of companies and have shares in the GSK group of companies. The authors declare no non-financial relationships and activities. All authors attest they meet the ICMJE criteria for authorship., (Copyright © 2022 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Background: Transplacentally transferred antibodies induced by maternal pertussis vaccination interfere with infant immune responses to pertussis primary vaccination. We evaluated whether this interference remains in toddlers after booster vaccination., Methods: In a prior phase IV, observer-blind, placebo-controlled, randomized study (NCT02377349), pregnant women in Australia, Canada and Europe received intramuscular tetanus-reduced-antigen-content diphtheria-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) at 27 0/7 -36 6/7 weeks' gestation, with crossover immunization postpartum. Their infants were primed (study NCT02422264) and boosted (at 11-18 months; current study NCT02853929) with diphtheria-tetanus-three-component acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTaP-HepB-IPV/Hib) and 13-valent pneumococcal conjugate vaccine. Immunogenicity before and after booster vaccination, and reactogenicity and safety of the booster were evaluated descriptively., Results: 263 (Tdap group) and 277 (control group) toddlers received a DTaP-HepB-IPV/Hib booster. Pre-booster vaccination, observed geometric mean concentrations (GMCs) for the three pertussis antigens and diphtheria were 1.4-1.5-fold higher in controls than in the Tdap group. No differences were observed for the other DTaP-HepB-IPV/Hib antigens. One month post-booster vaccination, booster response rates for pertussis antigens were ≥ 92.1% and seroprotection rates for the other DTaP-HepB-IPV/Hib antigens were ≥ 99.2% in both groups (primary objective). Higher post-booster GMCs were observed in controls versus the Tdap group for anti-filamentous hemagglutinin (1.2-fold), anti-pertussis toxoid (1.5-fold) and anti-diphtheria (1.4-fold). GMCs for the other DTaP-HepB-IPV/Hib antigens were similar between groups. Serious adverse events were reported for three toddlers (controls, not vaccination-related). One death occurred pre-booster (Tdap group, not vaccination-related)., Conclusions: As a consequence of interference of maternal pertussis antibodies with infant immune responses to pertussis primary vaccination, pertussis antibody concentrations were still lower in toddlers from Tdap-vaccinated mothers before DTaP-HepB-IPV/Hib booster vaccination. After the booster, antibody concentrations were lower for filamentous hemagglutinin and pertussis toxoid but not for pertactin. The clinical significance of this interference requires further evaluation., Clinical Trial Registration: ClinicalTrials.gov: NCT02853929., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BAN reports grants from the GSK group of companies (GSK) and support from other vaccine manufacturers. BC, MAC, NMes, NMey and SOK are employees of GSK, and BC, MAC and NMes own GSK restricted shares. FMT, JGS, SAH, TN and KPP’s institutions received grants from GSK during the conduct of the study. FMT’s institution received financial and non-financial support from Ablynx, Astra Zeneca, GSK, Jansen, MedImmune, MSD, Novavax, Pfizer, Regeneron, Roche, Sanofi Pasteur and Seqirus outside the submitted work. SAH received honoraria for participation in ad-hoc advisory committees for GSK and Sanofi Pasteur. TN received personal fees from GSK for serving as chair of advisory committees outside the submitted work. BT’s institution received grants from GSK during the conduct of the study; research grants for clinical trials were also given to his institution by Pfizer, MSD and Sanofi Pasteur. KPP received a fellowship from National Health and Medical Research Council for conducting the present work, and her institution received financial support from DBV Technologies, Medlmmune, Novavax and Pfizer for conducting trials outside the submitted work. ISC has received grants and/or honoraria as a consultant/advisor or to attend conferences and practical courses from GSK, Sanofi Pasteur, MSD and Pfizer outside the submitted work. JMMA reports receiving fees and non-financial support from GSK, as well as fees from Pfizer and MSD outside the submitted work. LK is working as consultant for GSK. MB, JB, MJCO, EEP, JJ, MMV, PK, PGM, JTRA, SR, ZS, MV, OGV and GVZ declare no conflicts of interest., (Copyright © 2021 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Aurora B kinase plays essential roles in mitosis. Its protein levels increase before the onset of mitosis and sharply decrease during mitosis exit. The latter decrease is due to a balance between the actions of the E3 ubiquitin ligase anaphase-promoting complex or cyclosome (activated by the Cdh1 adapter), and the deubiquitinating enzyme USP35. Aurora B also executes important functions in interphase. Abnormal modulation of Aurora B in interphase leads to cell cycle defects often linked to aberrant chromosomal condensation and segregation. Very little is however known about how Aurora B levels are regulated in interphase. Here we found that USP13-associates with and stabilizes Aurora B in cells, especially before their entry into mitosis. In order for USP13 to exert its stabilizing effect on Aurora B, their association is promoted by the Aurora B-mediated phosphorylation of USP13 at Serine 114. We also present evidence that USP13 instigates Aurora B deubiquitination and/or protect it from degradation in a non-catalytic manner. In addition, we report that genetic or chemical modulation of the cellular levels/activity of USP13 affects unperturbed cell-cycle progression. Overall our study unveils the molecular and cellular connections of the USP13-Aurora B axis, which potentially participates in the rewiring of the cell cycle happening in cancer cells.

Introduction Infants too young to be fully immunized are the most vulnerable to severe pertussis disease. To close this susceptibility gap, passive infant immunization through vaccination of pregnant women against pertussis was first introduced in 2011 in the United States and has been extended since then to more than 40 countries. Areas covered We conducted two systematic literature searches to describe the worldwide burden of pertussis disease in infants <6 months of age since 2005, and the effectiveness and impact of maternal pertussis vaccination in preventing infant pertussis since 2011. Expert opinion Pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Virtually all pertussis deaths occurred in this age group. Data from Africa, Eastern Mediterranean, and Asia were limited, but suggest a similar or higher disease burden than in Europe or the Americas. Estimates of effectiveness of second/third trimester pertussis vaccination in preventing pertussis disease in <2-3 months old infants were consistently high (69%-93%) across the observational studies reviewed, conducted in various settings with different designs. Maternal vaccination programs appear to be achieving their goal of reducing the burden of disease in very young infants. Plain language summary What is the context? Pertussis, also known as whooping cough, is a highly contagious disease of the respiratory tract. Infants too young to be fully vaccinated are at the highest risk of severe pertussis disease, hospitalization, and death. Vaccinating pregnant women against pertussis with a Tdap vaccine is recommended in more than 40 countries as a safe and effective strategy to protect infants for the first months of life. What is new? This review summarizes recent literature describing the burden of pertussis disease in infants worldwide prior to the introduction of maternal vaccination programs; pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Immunization of pregnant women with a Tdap vaccine can prevent about 70-90% of pertussis disease and up to 90.5% of pertussis hospitalizations in infants under 3 months of age. What is the impact? Limited available data suggest that incidence rates of pertussis disease after the introduction of Tdap maternal immunization have declined in infants. Current knowledge supports the implementation of Tdap maternal immunization programs.

Introduction: Maternal immunization with reduced antigen content tetanus-diphtheria-acellular pertussis (Tdap)-containing vaccines has been recommended to prevent infant pertussis. However, maternal antibodies may interfere with infant responses to routine immunization with diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccines, raising concerns of suboptimal protection after infant vaccination. We performed a narrative literature review to assess whether blunting occurs regardless of the manufacturer of maternal and infant vaccines. Because internationally agreed correlates of protection are lacking, the clinical significance of blunting is not yet fully understood. We have reviewed the evidence available to date., Areas Covered: Thirteen studies that evaluated blunting after maternal immunization and infant primary/booster series were identified. Blunting was observed with various combinations of Tdap- and DTaP-containing vaccines for maternal and pediatric immunization. Studies assessing the effectiveness of maternal Tdap immunization beyond the primary infant immunization series in England and in the United States suggested no evidence of a clinically relevant blunting effect so far., Expert Commentary: This review indicates that the phenomenon of blunting does not depend on the manufacturer/brand of the pertussis-containing vaccines used for immunizing mothers or children. Currently, there is no epidemiological evidence that children whose mothers received Tdap are at increased risk of pertussis after pediatric vaccinations, although longer follow-up is required.

Background: Pertussis immunization during pregnancy is recommended in many countries. Data from large randomized controlled trials are needed to assess the immunogenicity, reactogenicity and safety of this approach., Methods: This phase IV, observer-blind, randomized, placebo-controlled, multicenter trial assessed immunogenicity, transplacental transfer of maternal pertussis antibodies, reactogenicity and safety of a reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap) during pregnancy. Women received Tdap or placebo at 27-36 weeks' gestation with crossover ≤ 72-hour-postpartum immunization. Immune responses were assessed before the pregnancy dose and 1 month after, and from the umbilical cord at delivery. Superiority (primary objective) was reached if the lower limits of the 95% confidence intervals (CIs) of the pertussis geometric mean concentration (GMC) ratios (Tdap/control) in cord blood were ≥ 1.5. Solicited and unsolicited adverse events (AEs) and pregnancy-/neonate-related AEs of interest were recorded., Results: 687 pregnant women were vaccinated (Tdap: N = 341 control: N = 346). Superiority of the pertussis immune response (maternally transferred pertussis antibodies in cord blood) was demonstrated by the GMC ratios (Tdap/control): 16.1 (95% CI: 13.5-19.2) for anti-filamentous hemagglutinin, 20.7 (15.9-26.9) for anti-pertactin and 8.5 (7.0-10.2) for anti-pertussis toxoid. Rates of pregnancy-/neonate-related AEs of interest, solicited general and unsolicited AEs were similar between groups. None of the serious AEs reported throughout the study were considered related to maternal Tdap vaccination., Conclusions: Tdap vaccination during pregnancy resulted in high levels of pertussis antibodies in cord blood, was well tolerated and had an acceptable safety profile. This supports the recommendation of Tdap vaccination during pregnancy to prevent early-infant pertussis disease., Clinical Trial Registration: ClinicalTrials.gov: NCT02377349., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BC, MAC, NMes, NMey and SOK are employees of the GSK group of companies (GSK), and BC and NMes own GSK restricted shares. BT, MBEP, OGV, SAH and TN’s institutions received grants from GSK during the conduct of the study. KPP received grants from the National Health and Medical Research Council during the conduct of the study, and from MedImmune, Novavax and Pfizer outside the submitted work. FMT’s institution received financial support from GSK during the conduct of the study, as well as financial and non-financial support outside the submitted work; he also received personal fees from Pfizer, Novavax, MSD and Sanofi Pasteur; his institution also received financial support as trial fees from Ablynx, Jansen, Regeneron, Medimmune, Pfizer, MSD, Sanofi Pasteur, Novavax and Novartis, as well as non-financial support from Pfizer and MSD and grants from MSD and Astra Zeneca. LK is working as consultant for GSK. SAH is member of ad-hoc advisory committees for GSK and Sanofi Pasteur and he has a patent for novel triple adjuvant issued. AMG, CMP, GVZ, ICG, JEAF, MARZ, MCFM, MDCM, MMF, MV, PGM, PK, PM, YRE and ZS declare no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Pertussis immunization during pregnancy results in high pertussis antibody concentrations in young infants but may interfere with infant immune responses to post-natal immunization., Methods: This phase IV, multi-country, open-label study assessed the immunogenicity and safety of infant primary vaccination with DTaP-HepB-IPV/Hib and 13-valent pneumococcal conjugate vaccine (PCV13). Enrolled infants (6-14 weeks old) were born to mothers who were randomized to receive reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) during pregnancy (27 0/7 -36 6/7 weeks' gestation) with crossover immunization postpartum. All infants received 2 or 3 DTaP-HepB-IPV/Hib and PCV13 doses according to national schedules. Immunogenicity was assessed in infants pre- and 1 month post-primary vaccination. The primary objective was to assess seroprotection/vaccine response rates for DTaP-HepB-IPV/Hib antigens 1 month post-primary vaccination., Results: 601 infants (Tdap group: 296; control group: 305) were vaccinated. One month post-priming, seroprotection rates were 100% (diphtheria; tetanus), ≥98.5% (hepatitis B), ≥95.9% (polio) and ≥94.5% (Hib) in both groups. Vaccine response rates for pertussis antigens were significantly lower in infants whose mothers received pregnancy Tdap (37.5-77.1%) versus placebo (90.0-99.2%). Solicited and unsolicited adverse event rates were similar between groups. Serious adverse events occurred in 2.4% (Tdap group) and 5.6% (control group) of infants, none were vaccination-related., Conclusions: Pertussis antibodies transferred during pregnancy may decrease the risk of pertussis infection in the first months of life but interfere with the infant's ability to produce pertussis antibodies, the clinical significance of which remains unknown. Safety and reactogenicity results were consistent with previous experience., Clinical Trial Registration: ClinicalTrials.gov: NCT02422264., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [BAN reports grant from the GSK group of companies (GSK) and personal fees from Pfizer, MSD and Sanofi Pasteur. BC, MAC, NMes, NMey and SOK are employees of GSK, and BC and NMes own GSK restricted shares. FMT, KPP, OGV, SAH and TN’s institutions received grants from GSK during the conduct of the study. FMT’s institution received financial support from GSK during the conduct of the study, as well as financial and non-financial support outside the submitted work; he also received personal fees from Pfizer, Novavax, MSD and Sanofi Pasteur; his institution also received financial support as trial fees from Ablynx, Jansen, Regeneron, Medimmune, Pfizer, MSD, Sanofi Pasteur, Novavax and Novartis, as well as non-financial support from Pfizer and MSD and grants from MSD and AstraZeneca. JMMA reports receiving fees and non-financial support from GSK during the conduct of the study, as well as fees from GSK, Pfizer and MSD outside the submitted work. LK is working as consultant for GSK. SAH is member of ad-hoc advisory committees for GSK and Sanofi Pasteur and he has a patent for novel triple adjuvant issued. ACM, FOT, GVZ, JGS, JTRA, MB, MJCO, MMV, MV, PGM, PM and ZS declare no conflicts of interest.]., (Copyright © 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Reduced antigen diphtheria-tetanus-acellular pertussis (Tdap) vaccination is included in the maternal immunization program in Brazil since September 2014. We investigated associations between maternal Tdap vaccination and pregnancy-related adverse events (AEs) (gestational diabetes, pregnancy-related hypertension, and pregnancy hemorrhage) and neonatal AEs of interest (preterm birth and small for gestational age). This descriptive, observational, retrospective, single-center study in Brazil (NCT02757950) compared data from medical charts of 1203 pregnant women who received Tdap as part of the maternal immunization program and delivered between May 2015 and February 2017 (exposed cohort) and 1259 unvaccinated women who delivered between September 2012 and August 2014 (unexposed cohort). Index dates were defined as the time of vaccination (27-39 gestational weeks; exposed cohort) or 27 gestational weeks (unexposed cohort). Cumulative incidences were calculated as the number of women with each event between index and delivery dates divided by the total number of women with vaccination date available in the exposed cohort (N = 1199) or the total number of women in the unexposed cohort (N = 1259). Cumulative incidences per 1000 persons were 8.34 versus 17.47 for gestational diabetes, 9.17 versus 24.62 for pregnancy-related hypertension, 3.34 versus 15.09 for pregnancy hemorrhage, 53.38 versus 96.11 for preterm birth, and 57.55 versus 49.25 for small for gestational age in the exposed versus unexposed cohorts. No increased risk of pregnancy-related AEs or neonatal AEs of interest was found following maternal vaccination with Tdap. These results should be interpreted cautiously due to limitations inherent to retrospective observational studies.

TAX1BP1 is a novel ubiquitin-binding adaptor protein involved in the negative regulation of the NF-kappaB transcription factor, which is a key player in inflammatory responses, immunity and tumorigenesis. TAX1BP1 recruits A20 to the ubiquitinated signaling proteins TRAF6 and RIP1, leading to their A20-mediated deubiquitination and the disruption of IL-1-induced and TNF-induced NF-kappaB signaling, respectively. The two zinc fingers localized at its C-terminus function as novel ubiquitin-binding domains (UBZ, ubiquitin-binding zinc finger). Here we present for the first time both the solution and crystal structures of two classical UBZ domains in tandem within the human TAX1BP1. The relative orientation of the two domains is slightly different in the X-ray structure with respect to the NMR structure, indicating some degree of conformational flexibility, which is rationalized by NMR relaxation data. The observed degree of flexibility and stability between the two UBZ domains might have consequences on the recognition mechanism of interacting partners., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The CD2AP (CD2-associated protein) and CIN85 (Cbl-interacting protein of 85 kDa) adaptor proteins each employ three Src homology 3 (SH3) domains to cluster protein partners and ensure efficient signal transduction and down-regulation of tyrosine kinase receptors. Using NMR, isothermal titration calorimetry and small-angle X-ray scattering methods, we have characterized several binding modes of the N-terminal SH3 domain (SH3A) of CD2AP and CIN85 with two natural atypical proline-rich regions in CD2 (cluster of differentiation 2) and Cbl-b (Casitas B-lineage lymphoma), and compared these data with previous studies and published crystal structures. Our experiments show that the CD2AP-SH3A domain forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b. Like CD2AP, the CIN85-SH3A domain forms a type II complex with CD2, but a trimeric complex with Cbl-b, whereby the type I and II interactions take place at the same time. Together, these results explain how multiple interactions among similar SH3 domains and ligands produce a high degree of diversity in tyrosine kinase, cell adhesion or T-cell signaling pathways., (© 2013 FEBS.)