BACKGROUND:Norovirus is a major cause of acute gastroenteritis. Several vaccines are in development. Identifying a reliable immunological correlate of protection (CoP) would aid vaccine development and evaluation; however, no strong CoP has been established to date. METHODS:We evaluated the relationships between prechallenge genogroup I, genotype 1 (GI.1) and GII.4 norovirus antibodies and clinical outcomes in two human vaccine-challenge studies. We analyzed genotype-specific histo-blood group antigen blocking titers, serum IgA and IgG, and total antibody ELISA. We used Bayesian regression models to assess relationships between antibody levels and protection against infection, illness, and disease severity. RESULTS:Associations between antibody titers and protection were generally weak, and varied by genotype and vaccination status. GI.1 antibodies showed the strongest relationships, particularly among vaccinated participants, whereas naturally acquired GI.1 antibodies in unvaccinated individuals were weakly or not associated with protection. In contrast, GII.4 antibodies exhibited weak and inconsistent relationships among vaccinated participants, while unvaccinated participants showed only modest and more stable positive associations. CONCLUSIONS:Currently measured serum antibodies do not provide reliable and robust estimates of protection against norovirus clinical outcomes in all settings. Immune markers beyond serum antibody titers should be evaluated to identify more robust correlates of protection for norovirus.

Enterotoxigenic Escherichia coli (ETEC) diarrhea is associated with a high burden of disease globally, for which no licensed vaccine is available. A Phase 1, double-blind, dose-escalation (0.1-2.0 µg) study was conducted to evaluate the safety and immunogenicity of double mutant heat-labile toxin LTR192G/L211A (dmLT) delivered intradermally (ID) to healthy adults. Subjects received up to three immunizations at three-week intervals. The vaccine was safe, although it induced mild local and some gastrointestinal adverse events, as well as frequent hyperpigmentation at the injection site. High levels of serum IgG and IgA, LT neutralizing antibodies, and IgG and IgA antibodies in lymphocyte supernatant were elicited post-vaccination, most prominently at the largest dose (2.0 μg). Rates of responses were the highest in subjects who received the largest dose (2.0 μg) and multiple immunizations. The ETEC dmLT vaccine was safe and highly immunogenic, inducing long-lasting systemic and mucosal responses when administered by the ID route. Trial registration Clinical Trials NCT02531685.

Transcriptomic signatures were identified in human peripheral blood mononuclear cells (PBMCs) and breast milk lymphocyte (BML) cells induced by trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV) administered after delivery. We performed an RNA-Seq analysis on blood and breast milk samples from a subset of subjects enrolled in a randomized, double-blind controlled study in breastfeeding women who received either intranasal LAIV and intramuscular placebo, or intramuscular TIV and intranasal placebo (LAIV, n = 10 and TIV, n = 6). Differentially expressed genes, gene clusters, and enriched pathways were identified. We observed increased innate immune signaling responses in BML but not in PBMC at Day 28 for the LAIV group. We hypothesize that breastfeeding extended the innate response to LAIV via mucosal immunity. An association between an increased IgG antibody response in TIV vs. LAIV identified in the parent study using ELISA corresponded to IGHG1 immunoglobulin gene expression in Day 28 PBMCs.

Introduction Pandemic influenza vaccine development focuses on the hemagglutinin (HA) antigen for potency and immunogenicity. Antibody responses targeting the neuraminidase (NA) antigen, or the HA stalk domain have been implicated in protection against influenza. Responses to the NA and HA-stalk domain following pandemic inactivated influenza are not well characterized in humans. Material and methods In a series of clinical trials, we determine the vaccines' NA content and demonstrate that NA inhibition (NAI) antibody responses increase in a dose-dependent manner following a 2-dose priming series with AS03-adjuvanted influenza A(H7N9) inactivated vaccine (A(H7N9) IIV). NAI antibody responses also increase with interval extension of the 2-dose priming series or following a 5-year delayed boost with a heterologous adjuvanted A(H7N9) IIV. Neither concomitant seasonal influenza vaccination given simultaneously or sequentially, nor use of heterologous A(H7N9) IIVs in the 2-dose priming series had an appreciable effect on NAI antibody responses. Anti-HA stalk antibody responses were minimal and not durable. Conclusions We provide evidence for strategies to improve anti-neuraminidase responses which can be further standardized for pandemic preparedness. Clinical Trial Registry Numbers NCT03312231, NCT03318315, NCT03589807, NCT03738241.

Background The development of a universal influenza virus vaccine, to protect against both seasonal and pandemic influenza A viruses, is a long-standing public health goal. The conserved stalk domain of haemagglutinin (HA) is a promising vaccine target. However, the stalk is immunosubdominant. As such, innovative approaches are required to elicit robust immunity against this domain. In a previously reported observer-blind, randomised placebo-controlled phase I trial (NCT03300050), immunisation regimens using chimeric HA (cHA)-based immunogens formulated as inactivated influenza vaccines (IIV) -/+ AS03 adjuvant, or live attenuated influenza vaccines (LAIV), elicited durable HA stalk-specific antibodies with broad reactivity. In this study, we sought to determine if these vaccines could also boost T cell responses against HA stalk, and nucleoprotein (NP). Methods We measured interferon-gamma (IFN-gamma) responses by Enzyme-Linked ImmunoSpot (ELISpot) assay at baseline, seven days post-prime, pre-boost and seven days post-boost following heterologous prime:boost regimens of LAIV and/or adjuvanted/unadjuvanted IIV-cHA vaccines. Findings Our findings demonstrate that immunisation with adjuvanted cHA-based IIVs boost HA stalk-specific and NP-specific T cell responses in humans. To date, it has been unclear if HA stalk-specific T cells can be boosted in humans by HA-stalk focused universal vaccines. Therefore, our study will provide valuable insights for the design of future studies to determine the precise role of HA stalk-specific T cells in broad protection. Interpretation Considering that cHA-based vaccines also elicit stalk-specific antibodies, these data support the further clinical advancement of cHA-based universal influenza vaccine candidates. Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

ABSTRACT Background The MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated ~50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting efforts to improve this vaccine design might yield a vaccine suitable for licensure. A vaccine candidate employing nucleoside-modified mRNAs encoding HCMV gB and pentameric complex (PC) encapsulated in lipid nanoparticle, mRNA-1647, is currently in late-stage efficacy trials. Yet, its immunogenicity has not been compared to the partially-effective gB/MF59 vaccine. Methods We assessed neutralizing and Fc-mediated IgG effector antibody responses induced by mRNA-1647, a vaccine comprising an equal mass of 6 mRNAs encoding gB and PC antigens, in both HCMV seropositive and seronegative vaccinees from a first-in-human clinical trial through 1-year following 3 rd vaccination using a systems serology approach. Further, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative female adolescent gB/MF59 vaccine recipients. Results mRNA-1647 vaccination boosted pre-existing HCMV-specific IgG responses in seropositive vaccinees, including neutralizing and Fc-mediated effector antibody responses. In seronegative vaccinees, mRNA-1647 induced durable and functional HCMV-specific IgG responses. Elicited gB-specific IgG responses were lower than the PC-specific IgG responses. Additionally, gB-specific IgG and antibody-dependent cellular phagocytosis (ADCP) responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited robust neutralization and high antibody-dependent cellular cytotoxicity (ADCC) responses. Conclusions mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses. mRNA-1647-elicited gB-specific IgG responses were lower than PC-specific IgG responses and lower than those elicited by the partially effective gB/MF59. However, higher neutralization and ADCC responses were elicited by mRNA-1647 than gB/MF59. Clinical Trials Registration ClinicalTrials.gov ( NCT03382405 , mRNA-1647) and ( NCT00133497 , gB/MF59). Summary mRNA-1647 HCMV vaccine elicited polyfunctional and durable antibody responses in humans. While the mRNA-1647-elicited glycoprotein B (gB)-specific IgG responses were lower than that of the moderately-effective gB/MF59 vaccine, the pentameric complex (PC)-specific IgG responses were strong.

Background. Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown. Methods. We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 x 2 group), MIV with AS03 (AS03 x 2 group), unadjuvanted MIV (No Adj group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 group), and A/H7-naive (unprimed group). Participants were randomized to receive 1 dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing antibody assays. Results. We enrolled 304 participants: 153 received the adjuvanted boost and 151 received the unadjuvanted boost. At 21 days postvaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of >= 40 in the adjuvanted and unadjuvanted arms, respectively, were 88% and 49% in MF59 x 2 group, 89% and 75% in AS03 x 2 group, 59% and 20% in No Adj group, 94% and 55% in Adjx1group, and 9% and 11% in unprimed group. Conclusions. Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens. In the course of heterologous influenza A(H7N9) prime-boost vaccination at a 5-year interval, serologic responses were highest in participants primed and boosted with adjuvant-containing regimens. This finding has implications for influenza pandemic preparedness.

Cross-neutralizing aptamers targeting both HSV-1 and HSV-2 were developed by selecting against the ectodomains of glycoprotein D (gD) from both viruses in parallel as well as sequentially using the SELEX method. Since gD facilitates viral invasion, sterically blocking the host-receptor interaction prevents infection. Candidate aptamers were screened, and lead aptamers were identified that exhibited exceptional neutralizing activity against both viruses in vitro. The specificity of the aptamers was confirmed by comparing their activity to scrambled versions of themselves. Modifications of the lead compounds were tested to define critical motifs to guide development. Stability of the aptamers was increased using phosphorothioate backbone linkages, and 2’ methoxy substitutions of terminal and key internal bases. Aptamers were applied in a guinea pig vaginal HSV-2 infection model and found to reduce both the viral load of infected animals and the severity of the resulting disease. These results suggest that cross-neutralizing aptamers can be developed into on-demand antiviral interventions effective against both HSV-1 and HSV-2.

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the most prevalent human viruses worldwide. They are known to cause a variety of diseases including genital herpes, meningitis, encephalitis, cold sores and herpes stromal keratitis. The seropositive rate for HSV-1 is around 90%, whereas for HSV-2 it remains around 20-25% for the general adult population. The infections caused by these viruses remain difficult to study because a large proportion of infected individuals are asymptomatic. Furthermore, given the neurotropic characteristics of the virus, studies aimed at understanding the complex pathogenesis in humans is difficult. As a result, animal models have been developed to understand several characteristics of HSV biology, pathogenesis, disease and host responses to infection. These models are also commonly used as the first evaluation of new drugs and vaccines. There are several well-established animal models to study infection with HSV, including mice, guinea pigs and rabbits. Variables within the animal models depend on the species of animal, route of infection, viral strain, dosage, etc. This review aims at summarizing the most commonly used animal models to study HSV pathogenesis and therapies.

ABSTRACTBackgroundNon-pharmaceutical interventions to prevent the spread of coronavirus disease 2019 also decreased the spread of respiratory syncytial virus (RSV) and influenza. Viral diagnostic testing in patients with respiratory tract infections (RTI) is a necessary tool for patient management; therefore, sensitive and specific tests are required. This scoping literature review evaluated the analytical validity of commercially available sample-to- answer RSV diagnostic tests in different contexts.ContentPubMed and Embase were queried for studies reporting on the analytical validity of tests for RSV in patients with RTI (published January 2005–January 2021). Sensitivity and specificity of RSV tests and information on study design, patient, and setting characteristics were extracted from 77 studies that met predefined inclusion criteria. A literature gap was identified for studies of RSV tests conducted in adult-only populations (5.3% of total sub- records), and in outpatient (7.5%) or household (0.8%) settings. Overall, RSV tests with analytical time >30 min had higher sensitivity (62.5–100%) versus RSV tests with analytical time ≤ 30 min (25.7–100%), this sensitivity range could be partially attributed to the different modalities (antigen versus molecular) used. Molecular-based rapid RSV tests had higher sensitivity (66.7–100%) and specificity (94.3–100%) than antigen-based RSV tests (25.7– 100%; 80.3–100%).SummaryMolecular-based RSV tests should be considered for first-line use when possible, given their high sensitivity and specificity and that adults with RTI typically have low viral load, necessitating a highly sensitive test. This review benefits healthcare professionals by summarizing the diagnostic accuracy data available for commercially available RSV tests.IMPACT STATEMENTViral diagnostic testing in patients with respiratory tract infection is a powerful tool for patient management. This scoping literature review included 77 studies reporting the analytical validity of commercially available respiratory syncytial virus (RSV) diagnostic tests (published January 2005–January 2021) and examined the characteristics of such studies. The data suggest that molecular-based RSV tests have higher sensitivity and specificity than antigen-based tests, thus should be considered for first-line use for timely diagnosis and to detect infections in adults with low level viral load. Future studies should investigate the diagnostic accuracy of RSV tests in adults and in outpatient/household settings.

BACKGROUND Avian influenza A/H5N8 virus infections have been circulating widely in wild and domestic bird populations with transmission to a few human poultry workers. This phase 1, randomized, blinded trial evaluated the safety and immunogenicity of a monovalent inactivated influenza A/H5N8 virus vaccine (H5N8 IIV) given with and without AS03 or MF59 adjuvants. METHODS 275 healthy adults, ages 19-64 years, were randomized to one of five groups to receive two doses of 15 µg unadjuvanted influenza A/gyrfalcon/Washington/41088-6/2014(H5N8) (clade 2.3.4.4c) virus vaccine or two doses of 7.5 or 15 µg of vaccine adjuvanted with AS03 or MF59. Immunogenicity was assessed through 21 days following the second dose of vaccine using hemagglutination inhibition (HAI) and microneutralization (MN) assays for the homologous influenza A/H5N8 and three heterologous influenza A/H5 viruses. Safety was assessed through 1 year. RESULTS The vaccines were well tolerated. Only modest immune responses were seen following receipt of a single dose of vaccine. Seroprotection (HAI titers ≥40) was more common in groups that received AS03 plus 7.5 or 15 µg of vaccine (89% and 93%, respectively) compared to the MF59-adjuvanted groups (56% and 73%), while unadjuvanted vaccine showed a poor response (27%). Higher antigen content resulted in modestly improved immune responses. HAI and MN GMTs and seroconversion rates were low across all study groups for all three heterologous strains of influenza A/H5 virus. CONCLUSIONS AS03 or MF59-adjuvanted H5N8 IIV generated strong immunogenic responses following two doses. There was poor cross-reactivity for the three antigenically drifted H5N1 strains tested.

Herpes is a contagious life-long infection with persistently high incidence and prevalence, causing significant disease worldwide. Current therapies have efficacy against active HSV infections but no impact on the latent viral reservoir in neurons. Thus, despite treatment, disease recurs from latency and the infectious potential remains unaffected within patients. Here, efficacy of the helicase-primase inhibitor (HPI) IM-250 against chronic neuronal HSV infections utilizing two classic herpes in vivo latency/reactivation animal models (intravaginal guinea pig HSV-2 infection model and ocular mouse HSV-1 infection model) is presented. Intermittent therapy of infected animals with 4-7 cycles of IM-250 during latency silences subsequent recurrences analyzed up to 6 months. In contrast to common experience, our studies show that the latent reservoir is indeed accessible to antiviral therapy altering the latent viral reservoir such that reactivation frequency can be reduced significantly by prior IM-250 treatment. We provide evidence that antiviral treatment during HSV latency can reduce future reactivation from the latent reservoir, supporting a conceptual shift in the antiviral field, and reframing what is achievable with respect to therapy of latent neuronal HSV infections.

Background: The continuing evolution of influenza viruses poses a challenge to vaccine prevention, high-lighting the need for a universal influenza vaccine. We evaluated the safety and immunogenicity of one such candidate, Multimeric-001 (M-001), when used as a priming vaccine prior to administration of quadrivalent inactivated influenza vaccine (IIV4).Methods: Healthy adults 18 to 49 years of age were enrolled in a phase 2 randomized, double-blind placebo-controlled trial. Participants received two doses of either 1.0-mg M-001 or saline placebo (60 per study arm) on Days 1 and 22 followed by a single dose of IIV4 on about Day 172. Safety, reactogenic-ity, cellular immune responses and influenza hemagglutination inhibition (HAI) and microneutralization (MN) were assessed.Results: The M-001 vaccine was safe and had an acceptable reactogenicity profile. Injection site tender-ness (39% post-dose 1, 29% post-dose 2) was the most common reaction after M-001 administration. Polyfunctional CD4+ T cell responses (perforin-negative, CD107a-negative, TNF-a+, IFN-c+, with or with-out IL-2) to the pool of M-001 peptides increased significantly from baseline to two weeks after the second dose of M-001, and this increase persisted through Day 172. However, there was no enhancement of HAI or MN antibody responses among M-001 recipients following IIV4 administration.Conclusions: M-001 administration induced a subset of polyfunctional CD4+ T cells that persisted through 6 months of follow-up, but it did not improve HAI or MN antibody responses to IIV4. (clinical-trials.gov NCT03058692). (c) 2023 Elsevier Ltd. All rights reserved.

Background A vaccine that prevents cytomegalovirus (CMV) infection in women could reduce the incidence of congenital CMV infection, a major cause of neurodevelopmental disability. We aimed to assess the safety and efficacy of a replication-defective investigational CMV vaccine, V160, in CMV-seronegative women. Methods This phase 2b, randomised, double-blind, placebo-controlled study was conducted at 90 sites in seven countries (USA, Finland, Canada, Israel, Spain, Russia, and Australia). Eligible participants were generally healthy, CMV-seronegative, non-pregnant, 16-35-year-old women of childbearing potential with exposure to children aged 5 years or younger. Participants were randomly assigned using central randomisation via an interactive response technology system 1:1:1 to one of three groups: V160 three-dose regimen (V160 at day 1, month 2, and month 6), V160 two-dose regimen (V160 on day 1, placebo at month 2, and V160 at month 6), or placebo (saline solution at day 1, month 2, and month 6). The primary outcomes were the efficacy of three doses of V160 in reducing the incidence of primary CMV infection during the follow-up period starting 30 days after the last dose of vaccine using a fixed event rate design, and the safety and tolerability of the two-dose and three-dose V160 regimens. We planned to test the efficacy of a two-dose regimen of V160 in reducing the incidence of primary CMV infection only if the primary efficacy hypothesis was met. Analyses for the primary efficacy endpoint were performed on the per-protocol efficacy population; safety analyses included all randomly assigned participants who received study vaccine. The primary efficacy hypothesis was tested at prespecified interim and final analyses. The study was ongoing and efficacy data continued to accrue at the time of final testing of the primary efficacy hypothesis. Vaccine efficacy was re-estimated after final testing of the primary efficacy hypothesis based on all available efficacy data at end of study. This trial is registered at ClinicalTrials.gov (NCT03486834) and EudraCT (2017-004233-86) and is complete. Findings Between April 30, 2018, and Aug 30, 2019, 7458 participants were screened, of whom 2220 were randomly assigned to the V160 three-dose group (n=733), V160 two-dose group (n=733), or placebo group (n=734). A total of 523 participants in the V160 three-dose group and 519 in the placebo group were included in the final hypothesis testing. Of these, there were 11 cases of CMV infection in the V160 three-dose group and 20 cases in the placebo group. The vaccine efficacy for the V160 three-dose group was 44 center dot 6% (95% CI -15 center dot 2 to 74 center dot 8) at the final testing of the primary efficacy hypothesis, a result corresponding to failure to demonstrate the primary efficacy hypothesis. On the basis of this result, the study was terminated for futility. The re-estimate of vaccine efficacy for the V160 three-dose group based on all available efficacy data at end of study (556 participants in the V160 three-dose group and 543 in the placebo group) was 42 center dot 4% (95% CI -13 center dot 5 to 71 center dot 1). A total of 728 participants in the V160 three-dose group, 729 in the V160 two-dose group, and 732 in the placebo group were included in the safety analyses. The most common solicited injection-site adverse event was injection-site pain (680 [93%] in the V160 three-dose group, 659 [90%] in the V160 two-dose group, and 232 [32%] in the placebo group). The most common solicited systemic adverse event was fatigue (457 [63%] in the V160 three-dose group, 461 [63%] in the V160 two-dose group, and 357 [49%] in the placebo group). No vaccine-related serious adverse events or deaths were reported. Interpretation V160 was generally well tolerated and immunogenic; however, three doses of the vaccine did not reduce the incidence of primary CMV infection in CMV-seronegative women compared with placebo. This study provides insights into the design of future CMV vaccine efficacy trials, particularly for the identification of CMV infection using molecular assays. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD). Copyright (c) 2023 Elsevier Ltd. All rights reserved.

DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize β-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC50 for 24 h. These experiments identified a novel lead candidate, NPP-669. NPP-669 demonstrated efficacy against CMV infections in mice and AdV infections in hamsters following oral (p.o.) dosing at a dose of 1 mg/kg BID and 0.1 mg/kg QD, respectively. We further showed that NPP-669 at 30 mg/kg QD did not exhibit histological signs of toxicity in mice or hamsters. These data suggest that NPP-669 is a promising lead candidate for a broad-spectrum antiviral compound.

ImportanceCurrent data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders.ObjectiveTo identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection.Design, Setting, and ParticipantsThis secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023.ExposuresComorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment.Main Outcomes and MeasuresCoprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection.ResultsA total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001).Conclusions and RelevanceIn this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

Background We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study. Methods We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of >= 40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as >= 1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding. Results Of 76 participants given influenza virus challenge, 54 (71.1%) experienced MMID. Clinical illness was generally very mild. MMID attack rates among participants with baseline titers >= 40 by HAI and MN were 64.9% and 67.9%, respectively, while MMID attack rates among participants with baseline titers <40 by HAI and MN were 76.9% and 78.3%, respectively. The estimated odds of developing MMID decreased by 19% (odds ratio, 0.81 [95% confidence interval, .62-1.06]; P = .126) for every 2-fold increase in baseline HAI. There were no significant adverse events. Conclusions We achieved a 71.1% attack rate of MMID. High baseline HAI and MN were associated with protection from illness. In a multicenter controlled human infection model study, we inoculated 76 participants with influenza A/California/04/2009/H1N1pdm-like virus and safely achieved a 71.1% attack rate of mild-to-moderate influenza disease. High virus-specific hemagglutination inhibition and microneutralization titers were associated with protection from illness.

Herpes simplex virus 1 and 2 infections cause high unmet disease burdens worldwide. Mainly HSV-2 causes persistent sexually transmitted disease, fatal neonatal disease and increased transmission of HIV/AIDS. Thus, there is an urgent requirement to develop effective vaccines. We developed nucleic acid vaccines encoding a novel virus entry complex stabilising cell membrane fusion, 'virus-like membranes', VLM. Two dose intramuscular immunisations using DNA expression plasmids in a guinea pig model gave 100% protection against acute disease and significantly reduced virus replication after virus intravaginal challenge. There was also reduced establishment of latency within the dorsal root ganglia and spinal cord, but recurrent disease and recurrent virus shedding remained. To increase cellular immunity and protect against recurrent disease, cDNA encoding an inhibitor of chemokine receptors on T regulatory cells was added and compared to chemokine CCL5 effects. Immunisation including this novel human chemokine gene, newly defined splice variant from an endogenous virus genome, 'virokine immune therapeutic', VIT, protected most guinea pigs from recurrent disease and reduced recurrent virus shedding distinct from a gD protein vaccine similar to that previously evaluated in clinical trials. All DNA vaccines induced significant neutralising antibodies and warrant evaluation for new therapeutic treatments.

Purpose of review Influenza vaccines are the most useful strategy for preventing influenza illness, especially in the setting of the COVID-19 pandemic. For the coming year (2021/2022) all vaccines will be quadrivalent and contain two influenza A strains [(H1N1)pdm09-like and (H3N2)-like viruses] and two influenza B strains (Victoria lineage-like and Yamagata lineage-like viruses). However, the currently licensed have suboptimal efficacy due to the emergence of new strains and vaccine production limitations. In this review, we summarize the current recommendations as well as new advancements in influenza vaccinations. Recent findings Recent advances have been aimed at moving away from egg-based vaccines and toward cell culture and recombinant vaccines. This removes egg adaptations that decrease vaccine efficacy, removes the reliance on egg availability and decreases the time necessary to manufacture vaccines. However, even more radical changes are needed if we are to reach the ultimate goal of a universal vaccine capable of providing long-lasting protection against all or at least most influenza strains. We discuss various strategies, including using more stable influenza antigens such as the hemagglutinin stalk and internal proteins as well as new adjuvants, new vaccine formulations, and DNA/RNA-based vaccines that are currently being developed. Summary The currently available vaccines have suboptimal efficacy and do not provide adequate protection against drifted and shifted strains. Thus, the development of a universal influenza vaccine that induces long-lasing immunity and protects against a broad range of strains is crucial.

Abstract Background Preventing congenital cytomegalovirus infection (CMVi) is an important unmet need. Natural maternal immunity to CMV acquired prior to pregnancy appears to reduce fetal transmission. In a Phase 1 trial, V160, a replication-defective CMV vaccine expressing the pentameric complex, induced humoral and cell-mediated immune (CMI) responses comparable to natural immunity. Methods Healthy, CMV-seronegative women aged 16–35 years were randomized 1:1:1 to receive double-blind V160 in a 3- or 2-dose regimen or placebo. Primary and secondary endpoints were efficacy in reducing the incidence of CMVi with 3-dose or 2-dose regimens of V160 vs placebo, respectively, using a fixed-event design. Monthly urine and saliva samples were collected to identify CMVi by polymerase chain reaction (PCR) with a single positive sample considered evidence of infection. Immunoglobulin G (IgG) binding to glycoprotein B (gB) and CMV-specific neutralizing antibody (NAb) were measured in all participants, and CMI responses were measured in a subset. Injection-site and systemic adverse events (AEs) were collected for 5 days and 14 days, respectively, after each vaccination and serious AEs were collected for the trial duration. Results 2200 women from 7 countries were enrolled (of 7458 screened). Over 80% of participants received all doses, and compliance with saliva and urine samples was > 95%. Vaccine efficacy (VE) of 42.4% (95% CI -13.5, 71.1%) was demonstrated in the 3-dose group vs placebo. In the 2-dose group, VE was -32.0% (95% CI -135.0, 25.0%). Both the quantity and duration of CMV shedding in urine and saliva among cases of CMVi decreased in the 3-dose, but not the 2-dose group vs placebo. Both V160 regimens elicited humoral and CMI responses detected by CMV-specific NAb, gB IgG, and ELISpot, which peaked at Month 7 and continued to be detectable at Month 24. Mild to moderate AEs were more frequently reported in V160 vs placebo recipients, but no vaccine-related serious AEs or deaths were reported. Conclusion V160 was well tolerated and immunogenic, but neither the 3-dose nor 2-dose regimen demonstrated significant efficacy against CMVi as defined in this trial. The quantity and duration of CMV shedding was reduced in the 3-dose group, suggesting V160 may improve immune control of viral replication after CMVi. Disclosures Rituparna Das, MD, Merck & Co, Inc. (Employee) Daniel Blazquez-Gamero, MD, MSD (Other Financial or Material Support, Fees for lectures in educational activities) Soren Gantt, MD, Altona Diagnostics (Research Grant or Support)Merck (Consultant, Grant/Research Support)Meridian Biosciences (Research Grant or Support)Moderna (Consultant, Research Grant or Support)VBI Vaccines Inc (Research Grant or Support) Oliver Bautista, PhD, Merck & Co, Inc. (Employee) Karen Beck, RN, BSN, Merck & Co, Inc. (Employee) Anthony Conlon, PhD, Merck & Co, Inc. (Employee) Daniel Rosenbloom, PhD, Merck & Co, Inc. (Employee) Dai Wang, PhD, Merck & Co, Inc. (Employee) Michael Ritter, BA, Merck & Co, Inc. (Employee) Beth Arnold, MS, Merck & Co, Inc. (Employee, Shareholder) Paula Annunziato, MD, Merck & Co, Inc. (Employee) Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder)