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Influenza epidemics cause substantial morbidity. The seasonal vaccine, an important control measure, is not completely efficacious. This trial assessed the efficacy of a recombinant seasonal vaccine (made in a cell culture rather than with viruses grown in eggs). Reducing the burden of influenza disease requires improved vaccines, and a recombinant influenza vaccine may contribute to this public-health goal. 1 This vaccine contains recombinant hemagglutinin (HA) proteins produced in a serum-free medium by expres SF+ cells. These cells contain recombinant baculovirus vectors carrying genes that code for HA. The process yields recombinant HA that is genetically identical to the selected influenza strains without extraneous egg proteins, formaldehyde, antibiotics, or preservatives. Influenza viruses are grown in eggs to produce the inactivated influenza vaccine (IIV); these viruses typically contain mutations in the genes that code for HA that may reduce vaccine effectiveness. . . .

NVX-CoV2373 is a vaccine containing a full-length stabilized recombinant spike protein trimer that is administered in two doses 3 weeks apart along with a saponin-based adjuvant. In a randomized trial, approximately 20,000 participants received the vaccine and 10,000 a placebo. Vaccine efficacy against infection was 90%, and reactogenicity was similar to that of other Covid-19 vaccines.

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use. Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.

•NVX-CoV2373 manufacturing lots are consistently immunogenic and well-tolerated.•NVX-CoV2373 can be used as a first booster dose or a later booster dose.•NVX-CoV2373 is also immunogenic against Omicron BA.1/BA.5 SARS-CoV-2 variants. To combat the SARS-CoV-2 pandemic, multiple vaccines using different manufacturing platforms have been developed, including NVX-CoV2373 (an adjuvanted recombinant protein vaccine). As SARS-CoV-2 variants have emerged, some of which evade vaccine-induced immunity, introduction of vaccine booster doses has become critical. Employing different vaccine types for primary series vaccination and boosting could expand vaccine coverage and access. This study assessed whether NVX-CoV2373 would induce robust responses when used as a booster. The 2019nCoV-307 study was a phase 3, randomized, observer-blinded trial evaluating immunogenicity and safety of NVX-CoV2373 in previously vaccinated adults aged 18–49 years in the United States (NCT05463068). Participants were randomized 1:1:1 to receive one intramuscular injection of NVX-CoV2373 from one of three different manufacturing lots. Immunogenicity was assessed by immunoglobulin G (IgG) and neutralizing antibodies (NAb). These responses were compared for the three lots, and for participants with primary series with or without a prior booster dose of the mRNA-1273, BNT162b2, Ad26.COV2.S, or NVX-CoV2373 COVID-19 vaccines. A total of 911 participants were randomized between July 11 and 13, 2022, with 905 being assessed for safety and 848 for immunogenicity. Immunogenicity of NVX-CoV2373 met prespecified equivalence criteria between lots, and the booster dose was well-tolerated. NVX-CoV2373 induced robust IgG and NAb responses when used as a first or later booster dose, regardless of primary series vaccine type. Seroconversion rates were also similar across previous vaccine types. Induced antibodies were strongly reactive, even to the immune-evasive Omicron BA.1 and BA.5 variants. NVX-CoV2373 showed consistent immunogenicity between lots, with no new safety signals identified. Use of NVX-CoV2373 as a booster dose (first or later) is supported.

Background. Agents that block the CCR5 coreceptor for human immunodeficiency virus (HIV) have demonstrated potent antiretroviral activity. In early clinical studies, the CCR5 antagonist vicriviroc proved to be a safe and effective component of combination antiretroviral therapy. Methods. This double-blind, dose-ranging, phase 2 trial randomized subjects to receive 30 mg or 20 mg of vicriviroc or placebo once daily plus re-optimized background therapy containing a protease inhibitor with ritonavir. Subjects were adults infected with CCR5-tropic HIV who were experiencing failure of triple antiretroviral regimens. The primary end point was mean change in baseline log10 HIV RNA level at 48 weeks, based on an intent-totreat analysis. Results. One hundred fourteen persons received vicriviroc at 30 mg (n = 39), vicriviroc at 20 mg (n = 40), or placebo (n = 35). The mean change in baseline HIV RNA level at week 48 was −1.77 log10 copies/mL for 30 mg of vicriviroc and −1.75 log10 copies/mL for 20 mg of vicriviroc, compared with −0.79 log10 copies/mL for placebo (P = .002 and P = .003, respectively, compared with placebo). Mean CD4 counts increased by 102, 136, and 63 cells/mm3 for 30 mg vicriviroc, 20 mg vicriviroc, and placebo, respectively (P = .260 and P = .039, respectively, compared with placebo). Rates of adverse events (mostly mild-to-moderate) were 111.4, 112.5, and 147.4 events per 100 subject-years, respectively. Conclusions. Vicriviroc administered with a protease inhibitor plus ritonavir-containing regimen shows potent antiretroviral and immunologic activity sustained over 48 weeks in treatment-experienced patients. Clinical trials registration. NCT00243230.

PREVENT-19, the pivotal phase 3 trial of the Novavax adjuvanted, recombinant spike protein COVID-19 vaccine (NVX-CoV2373), demonstrated that the vaccine was well tolerated and efficacious (vaccine efficacy, VE = 90%) for the prevention of symptomatic COVID-19. In the trial, participants were randomly assigned in a 2:1 ratio to receive 2 doses of NVX-CoV2373 or placebo 21 days apart. Throughout the study, the predominant SARS-CoV-2 variant was alpha, but additional variants were in circulation (i.e., beta, gamma, epsilon, and iota). VE among the per-protocol efficacy analysis population was calculated according to pre-specified disease severity (mild, moderate, or severe) criteria, but the impact on the risk of COVID-19–associated hospitalization was not specifically investigated. During this analysis period (January 25, 2021, to April 30, 2021 [95 days]), 4 hospitalizations occurred among the 77 events analyzed for the primary endpoint using the per-protocol population, 0 among vaccine recipients and 4 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 28.8, 100). Among an expanded efficacy population, also identified post hoc, which included COVID-19–associated hospitalizations without a requirement for diagnostic polymerase chain reaction testing performed at the study central laboratory, 12 total hospitalizations were identified, 0 among vaccine recipients and 12 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 83.1, 100). These additional data from the PREVENT-19 trial provide relevant public health information concerning the attributes of NVX-CoV2373.

Randomized comparison of immunogenicity and safety of quadrivalent recombinant versus inactivated vaccine in young adults showed overall comparable antibody titers to vaccine strains, including higher responses to influenza A/H3N2 consistent with better efficacy previously reported in adults 50 or older. Abstract Background Seasonal influenza vaccines are transitioning to quadrivalent formulations including the hemagglutinins of influenza A subtypes H1N1 and H3N2 and B lineages Yamagata and Victoria. Methods A new quadrivalent recombinant influenza vaccine (RIV4) was compared directly with a standard-dose, egg-grown, quadrivalent-inactivated influenza vaccine (IIV4) for immunogenicity and safety in adults 18–49 years of age. The coprimary endpoints for noninferiority were hemagglutination inhibition seroconversion rates and postvaccination geometric mean titer ratios for each antigen using US regulatory criteria. Reactogenicity solicited for 7 days, other safety events collected for 28 days, and serious or medically attended adverse events collected for 6 months after vaccination comprised the safety evaluation. Results The immunogenicity of RIV4 was comparable to that of IIV4; the coprimary noninferiority criteria were met for 3 antigens, and the antibody responses to the fourth antigen, influenza B/Brisbane/60/2008, were low in each group, making comparisons uninterpretable. Systemic and injection site reactions were mild, transient, and similar in each group, whereas none of the spontaneously reported adverse events, serious or nonserious, were considered related to study vaccine. Conclusions This first head-to-head comparison of recombinant versus inactivated quadrivalent influenza vaccines in 18–49 year old adults showed comparable immunogenicity, safety, and tolerability for both vaccines.

NVX-CoV2373, a recombinant SARS-CoV-2 spike (rS) protein vaccine with Matrix-M® adjuvant, has been authorized for use in adults and adolescents. PREVENT-19 (NCT04611802/2019nCoV-301), a pivotal phase 3, randomized, placebo-controlled trial demonstrated robust efficacy of a primary, 2-dose series of NVX-CoV2373 against COVID-19. Protocol expansions to PREVENT-19 included enrollment of adolescents (aged 12 to <18 years) and administration of 3rd and 4th doses of NVX-CoV2373 to adults and adolescents. Participants randomized 2:1 received NVX-CoV2373 or placebo 21 days apart; 3rd and 4th doses were administered ≥6 months after the preceding dose. Secondary and additional assessments included post–3rd- and 4th-dose immune responses (neutralizing antibody [nAb], anti-rS IgG, human angiotensin-converting enzyme-2–receptor binding inhibition [hACE2-RBI]) and response durability (post–3rd dose) to ancestral virus; cross-reactivity to Omicron subvariants; safety; and reactogenicity. Immune responses were observed against ancestral virus after two doses of NVX-CoV2373 but not after placebo. In both adults and adolescents, additional doses of NVX-CoV2373 increased nAb titers, anti-rS IgG levels, and hACE2-RBI; durable responses were recorded 8 months post 3rd dose. nAb responses post 3rd dose were noninferior to those post primary series. Cross-reactivity to BA.5 and BQ.1.1 variants was also observed, with anti-rS IgG levels post 3rd or 4th dose exceeding previously reported correlates of protection. Additional doses of NVX-CoV2373 were well tolerated, with no new safety signals. NVX-CoV2373 elicited robust and durable humoral immune responses to ancestral SARS-CoV-2 as a 3rd and 4th dose after the primary series in adults and adolescents. Cross-reactivity to relevant variants provides insight into potential protection against antigenically related, but shifted, viral strains. Additional doses of NVX-CoV2373 were well tolerated with no new safety signals. These results support the utility of this vaccine platform and continued updates, based on currently circulating strains, to help effectively combat SARS-CoV-2 infection. •NVX-CoV2373 elicits robust and durable humoral immune responses to SARS-CoV-2.•3rd and 4th subsequent homologous doses are immunogenic and well tolerated.•NVX-CoV2373 was cross-reactive to variants circulating at the time of this study.

•We evaluated baculovirus-expressed recombinant H5 hemagglutinin vaccine with the adjuvant GLE/SE.•Adjuvanted vaccine was substantially more immunogenic at all dose levels than the unadjuvanted vaccine.•Even at the lowest dose of vaccine administered, serum HAI antibody responses of ≥1:40 were seen in 72% of subjects.•GLA/SE is an effective adjuvant for recombinant H5 HA.•Baculovirus-expressed HA vaccine has promise for pandemic preparedness as well. Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE). Healthy adults 18–49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135μg or 45μg, or rHA 45μg, 15μg, 7.5μg or 3.8μg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42. 392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50–70% of rHA+GLA/SE recipients and 4–9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% and 15% in the unadjuvanted 135μg and 45μg groups, and 82%, 75%, 66%, and 72% in those receiving 45μg, 15μg, 7.5μg, or 3.8μg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45μg, 15μg, 7.5μg, or 3.8μg with GLA/SE groups, respectively. rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control.

•Age, sex, and race/ethnicity do not affect efficacy against symptomatic COVID-19.•Common underlying health conditions also do not impact vaccine efficacy.•There is no association between household or workplace exposure and vaccine efficacy.•Vaccines delivered through different platforms demonstrate overall high efficacy. Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802.