Immunogenicity and safety of a monovalent omicron XBB.1.5 SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose in US adults: interim analysis of a single-arm phase 2/3 study.

Authorities globally recommended a monovalent omicron XBB.1.5-based COVID-19 vaccine for the 2023-24 season. The Novavax COVID-19 vaccine, NVX-CoV2601, contains XBB.1.5 recombinant spike protein, based on an authorised prototype vaccine (NVX-CoV2373) technology. We aimed to determine whether a single dose of NVX-CoV2601 versus NVX-CoV2373 (from a previous study [2019nCoV-311 part 2]) produced superior neutralising antibody (nAb) responses, and non-inferior seroresponse rates to XBB.1.5, after three or more previous mRNA-based COVID-19 vaccinations. In part 1 of this single-arm, phase 2/3 study (2019nCoV-313), participants aged 18 years or older who had been previously vaccinated with three or more doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) were enrolled across 30 US centres (research groups and universities) located across 20 states. Participants received one intramuscular injection of NVX-CoV2601 (5 μg XBB.1.5 spike plus 50 μg Matrix-M adjuvant). Coprimary endpoints were superiority of baseline-adjusted nAb geometric mean XBB.1.5 titres (adjusted GMTs), with superiority declared when the lower bound of the 95% CI for the GMT ratio (GMTR) was greater than 1, and non-inferiority of seroresponse rates, with non-inferiority declared when the lower bound of the 95% CI for the seroresponse rate difference was greater than -10%, on day 28; comparisons were made for NVX-CoV2601 administered in this study versus NVX-CoV2373 administered in part 2 (group G) of the 2019nCoV-311 study. Coprimary endpoints were assessed in the per-protocol immunogenicity set (ie, all participants who received study vaccine, underwent 28 days of follow-up, had day 0 and day 28 samples available, and had no major protocol deviations). Safety was a secondary endpoint and included assessments of solicited treatment-emergent adverse events up to 7 days and unsolicited treatment-emergent adverse events up to 28 days after vaccination in the safety analysis set (ie, all participants who received study vaccine). Here we report the prespecified interim analysis of immunogenicity and safety up to day 28. This study is registered with ClinicalTrials.gov, NCT05975060, and is now complete. Between Sept 7 and Sept 8, 2023, 380 individuals were screened, of whom 332 were enrolled and received study vaccine. At the 28-day interim analysis database lock (Jan 17, 2023), the per-protocol analysis sets included 309 (93%) of 332 NVX-CoV2601 recipients and 227 (90%) of 252 NVX-CoV2373 recipients. Mean age of NVX-CoV2601 recipients was 52·1 years (SD 16·1); 192 (62%) of 309 were female and 117 (38%) were male. Mean age of NVX-CoV2373 recipients was 42·2 years (13·4); 128 (56%) of 227 were female and 99 (44%) were male. At day 28, the baseline-adjusted nAb GMT for NVX-CoV2601 was 905·9 (95% CI 807·1-1016·8) and for NVX-CoV2373 was 156·6 (137·0-179·0); the between-group adjusted GMTR was 5·8 (95% CI 4·9-6·9). In the per-protocol immunogenicity set, seroresponse rates were 64% (196 of 305) among recipients of NVX-CoV2601 and 7% (16 of 227) among recipients of NVX-CoV2373, with a seroresponse rate difference of 57% (95% CI 51-63). In the NVX-CoV2601 group, within 7 days, solicited local treatment-emergent adverse events were reported in 189 (57%) of 332 participants (including one [<1%] grade 3 or worse event; tenderness) and solicited systemic treatment-emergent adverse events were reported in 158 (48%) participants (including four [1%] participants with one or more grade 3 events; malaise [n=3], headache [n=2], fatigue [n=1], and muscle pain [n=1]). The most common solicited treatment-emergent adverse events were tenderness (171 [52%]) and pain (98 [30%]) at the injection site, fatigue (97 [29%]), and muscle pain (97 [29%]). Up to day 28, unsolicited adverse events considered related to study vaccination in the NVX-CoV2601 group occurred in five (2%) participants (one for each of asthma, axillary pain, diarrhoea, hypertension [which was medically attended], and presyncope). No serious adverse events due to study product, adverse events of special interest, or deaths due to study product occurred, and no study discontinuations due to treatment-emergent adverse events occurred. The coprimary endpoints were met, and NVX-CoV2601 was well tolerated. These interim data support NVX-CoV2601 use per guidance for XBB.1.5-directed COVID-19 vaccines and demonstrate the adaptability of this vaccine platform for updated SARS-CoV-2 spike proteins. Novavax.

Alves K ，Kotloff K ，McClelland RS ，Kouassi A ，Plested JS ，Kalkeri R ，Zhu M ，Cloney-Clark S ，Cai Z ，Smith K ，Kaba M ，Nelson J ，Hammershaimb EA ，Mallory RM ，Noriega F ，2019nCoV-313 Study Investigators ... -  《-》

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

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. 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. 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. 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. Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Sridhar S ，Joaquin A ，Bonaparte MI ，Bueso A ，Chabanon AL ，Chen A ，Chicz RM ，Diemert D ，Essink BJ ，Fu B ，Grunenberg NA ，Janosczyk H ，Keefer MC ，Rivera M DM ，Meng Y ，Michael NL ，Munsiff SS ，Ogbuagu O ，Raabe VN ，Severance R ，Rivas E ，Romanyak N ，Rouphael NG ，Schuerman L ，Sher LD ，Walsh SR ，White J ，von Barbier D ，de Bruyn G ，Canter R ，Grillet MH ，Keshtkar-Jahromi M ，Koutsoukos M ，Lopez D ，Masotti R ，Mendoza S ，Moreau C ，Ceregido MA ，Ramirez S ，Said A ，Tavares-Da-Silva F ，Shi J ，Tong T ，Treanor J ，Diazgranados CA ，Savarino S ... -  《-》

Safety and immunogenicity of mRNA-1345 RSV vaccine coadministered with an influenza or COVID-19 vaccine in adults aged 50 years or older: an observer-blinded, placebo-controlled, randomised, phase 3 trial.

Coadministration of a respiratory syncytial virus (RSV) vaccine with seasonal influenza or SARS-CoV-2 vaccines could reduce health-care visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease. The RSV mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in the ConquerRSV trial in adults aged 60 years and older. We aimed to evaluate the safety and immunogenicity of mRNA-1345 coadministered with a seasonal influenza vaccine or SARS-CoV-2 mRNA vaccine. We conducted a two-part, phase 3, observer-blinded, placebo-controlled, randomised trial in medically stable adults aged 50 years or older in the USA. In part A, participants were randomly assigned in a 7:10:10 ratio to receive 50 μg mRNA-1345 plus placebo (0·9% sodium chloride) or coadministered with 60 μg of a standard-dose quadrivalent inactivated influenza vaccine (SIIV4), or SIIV4 plus placebo. In part B, participants were randomly assigned in a 1:1:1 ratio to receive 50 μg mRNA-1345 plus placebo or coadministered with 50 μg SARS-CoV-2 mRNA-1273.214 (bivalent [Wuhan-Hu-1 plus omicron BA.1]), or mRNA-1273.214 plus placebo. Random allocation in both parts was stratified by age group (50-59 years, 60-74 years, and ≥75 years) and used interactive response technology. The coprimary objectives in each part were safety in the safety set throughout the study and non-inferiority for six immunogenicity endpoints in the per-protocol set comparing coadministered versus individual vaccines on day 29. Immunogenicity endpoints were geometric mean titre (GMT) ratios (GMRs) of RSV-A neutralising antibodies (nAbs; in parts A and B), GMRs of haemagglutination inhibition (HAI) titres to each of the four influenza strains in SIIV4 (A/Victoria/2570/2019 [H1N1]pdm09-like virus [A/H1N1], A/Cambodia/e0826360/2020 [H3N2]-like virus [A/H3N2], B/Washington/02/2019-like virus [B/Victoria], and B/Phuket/3073/2013-like virus [B/Yamagata]; in part A), GMRs of nAbs against SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B), and differences in seroresponse rates for nAbs against RSV-A (parts A and B) and SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B). Non-inferiority was declared when the lower bound of the 95% CI for GMRs was greater than 0·667 and for seroresponse rate differences was greater than -10%. This trial is registered with ClinicalTrials.gov (NCT05330975) and is ongoing. Between April 1 and June 9, 2022, 1631 participants were randomly allocated in part A and 1623 received vaccinations on day 1 (685 [42%] received mRNA-1345 plus SIIV4, 249 [15%] mRNA-1345 plus placebo, and 689 [42%] SIIV4 plus placebo). Due to an interactive response technology error, the mRNA-1345 plus placebo group was smaller than planned (249 vs 420 participants). Of the 1623 participants in the safety set, 877 (54%) were female and 746 (46%) were male. Between July 27 and Sept 28, 2022, 1691 participants were randomly allocated in part B and 1681 received vaccinations on day 1 (564 [34%] received mRNA-1345 plus mRNA-1273.214, 558 [33%] mRNA-1345 plus placebo, and 559 [33%] mRNA-1273.214 plus placebo). Among the 1681 participants in the safety set, 924 (55%) were female and 757 (45%) were male. The reactogenicity profiles of the coadministered regimens were generally similar to the profiles when the vaccines were administered alone. As of the 6-month and 7-month follow-up times for parts A and B, respectively, no serious adverse events, adverse events of special interest, discontinuations due to adverse events, or fatal events considered related to study vaccination were reported. In part A, the GMR of nAbs against RSV-A in the mRNA-1345 plus SIIV4 group versus the mRNA-1345 alone group was 0·81 (95% CI 0·67 to 0·97), and the seroresponse rate difference in nAbs against RSV-A between the groups was -11·2% (95% CI -17·9 to -4·1). GMRs of anti-HAI titres in the mRNA-1345 plus SIIV4 versus SIIV4 alone groups were 0·89 (0·77 to 1·03) for A/H1N1, 0·97 (0·86 to 1·09) for A/H3N2, 0·93 (0·82 to 1·05) for B/Victoria, and 0·91 (0·81 to 1·02) for B/Yamagata. In part B, the GMR of nAbs against RSV-A in the mRNA-1345 plus mRNA-1273.214 versus the mRNA-1345 alone groups was 0·80 (95% CI 0·70 to 0·90), and the seroresponse rate difference was -4·4% (95% CI -9·9 to 1·0). Comparing the mRNA-1345 plus mRNA-1273.214 group with the mRNA-1273.214 alone group, the GMR of nAbs was 0·96 (0·87 to 1·06) for the ancestral (D614G) virus and 1·00 (0·89 to 1·14) for omicron BA.1; seroresponse rate differences were 0·2% (95% CI -6·0 to 6·3) for SARS-CoV-2 ancestral and -0·9% (-6·6 to 4·7) for omicron BA.1. Coadministered mRNA-1345 plus SIIV4 or mRNA-1273.214 vaccines had acceptable safety profiles and elicited mostly non-inferior immune responses compared to individual vaccines in adults aged 50 years or older; only the seroresponse rate difference in nAbs against RSV-A in part A did not meet the non-inferiority criterion. Overall, these data support coadministration of mRNA-1345 with these vaccines in this population; longer-term evaluation continues in this study. Moderna.

Goswami J ，Cardona JF ，Hsu DC ，Simorellis AK ，Wilson L ，Dhar R ，Tomassini JE ，Wang X ，Kapoor A ，Collins A ，Righi V ，Lan L ，Du J ，Zhou H ，Stoszek SK ，Shaw CA ，Reuter C ，Wilson E ，Miller JM ，Das R ，study investigators ... -  《-》

Immunogenicity, safety, and reactogenicity of concomitant administration of the novavax vaccine against Omicron XBB.1.5 (NVX-CoV2601) and a 20-valent pneumococcal conjugate vaccine in adults aged ≥60 years: A randomised, double-blind, placebo-controlled,

There is conflicting evidence as to whether the combined administration of two vaccines can lead to poorer immunogenicity and reactogenicity. The co-administration of the Omicron-adapted COVID-19 vaccine from Novavax (NVX-CoV2601) and a 20-valent pneumococcal conjugate vaccine (PCV20) has not been previously investigated. In this randomised, double-blind, placebo-controlled, non-inferiority trial, immunocompetent participants aged ≥60 years were randomised in a 1:1:1:1 ratio to four groups: NVX-CoV2601 plus PCV20 (combination group); NVX-CoV2601 plus placebo (NVX-only group); PCV20 plus placebo (PCV20-only group); or placebo plus placebo (placebo group). The primary outcome was Omicron-specific anti-spike protein IgG ELISA units at day 28 in the combination group compared with the NVX-only group. Non-inferiority was established if the lower limit of the two-sided 95% CI of the geometric mean titre ratio was above the non-inferiority margin of 0.67. Secondary outcomes included anti-pneumococcal capsular polysaccharide (PCP) IgG ELISA units. Solicited local and systemic adverse events were collected for 7 days after vaccination. This study was registered with ClinicalTrials.gov, number NCT05767606, and the EU Clinical Trials Register, EudraCT number 2022-004118-12. All 256 randomised participants completed the study. The baseline characteristics were similar in the four groups. Overall, the median age was 64 (IQR 61 to 69) and 105 (41%) of 256 were male. At day 28, the geometric mean anti-spike protein IgG ELISA units were 534 U/mL (95% CI 432-660) in the combination group and 556 U/mL (95% CI 460-672) in the NVX-only group, resulting in a geometric mean titre ratio of 0.96 (95% CI 0.73-1.27), thereby meeting the criteria for non-inferiority. Anti-PCP IgG ELISA units at day 28 were 507 U/mL (95% CI 416-619) in the combination group and 592 U/mL (95% CI 485-723) in the PCV20-only group. Local and systemic reactogenicity was similar in the three active treatment groups. No safety concerns or serious adverse events were observed. Immunogenicity following co-administration of NVX-CoV2601 with PCV20 was non-inferior to administration of NVX-CoV2601 alone. Given the similar safety and reactogenicity profile, our findings may help to overcome concerns about concomitant vaccination and pave the way for combination vaccines. Novavax.

Jorda A ，Prager M ，Pracher L ，Haselwanter P ，Jackwerth M ，Al Jalali V ，Yildiz E ，Leutzendorff A ，Weber M ，Yourieva S ，Kammerer P ，Pecho T ，Decaminada A ，Ederer L ，Wiedermann U ，Weseslindtner L ，Redlberger-Fritz M ，Bergmann F ，Zeitlinger M ... -  《-》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》