Nipah virus (NiV) is a highly pathogenic, zoonotic paramyxovirus with pandemic potential. No licensed vaccines or treatments are available. Therefore, we conducted a phase 1, first-in-human, open-label, dose-escalation trial of a lipid nanoparticle mRNA vaccine, mRNA-1215, encoding a chimeric pre-fusion F (Pre-F) protein linked to glycoprotein G of a NiV Malaysian strain. Forty healthy adults, who met eligibility criteria, were enrolled into the 10-, 25-, 50- or 100-μg dose groups with ten participants per group. Each participant received two doses of mRNA-1215, intramuscularly, at a 4-week interval except for one participant in the 10-μg dose group who received only the first dose. All participants remained in the study until their final study visit. The primary outcome of vaccine safety and tolerability was determined by prespecified end points: the frequency and severity of solicited local and systemic adverse events (AEs), unsolicited AEs, safety laboratory measures, medically attended AEs, AEs of special interest, new chronic medical conditions and serious AEs. The most frequently reported local and systemic AEs were mild pain and tenderness at the injection site (n  = 33; 82%) and mild malaise (n  = 16; 40%), respectively. Overall, the vaccine was well tolerated. No serious AEs occurred during the study. mRNA-1215 elicited robust Pre-F and G binding antibody titers, the prespecified secondary end points. An exploratory analysis found that mRNA-1215 elicited neutralizing titers by 2 weeks after the prime in all dose groups. Responses increased after the boost and remained elevated for at least 1 year after vaccination. These findings demonstrate an initial overall favorable safety profile and immunogenicity results for a first-in-human, structure-based, chimeric mRNA Nipah virus vaccine. mRNA-1215 is a promising vaccine candidate for continued clinical development for populations at risk for regional and potentially larger outbreaks caused by Nipah virus. ClinicalTrials.gov identifier: NCT05398796 .

To expand the supply of the modified vaccinia Ankara (MVA) smallpox/mpox vaccine, fractional doses administered intradermally (ID) have been considered as alternatives to the standard dose given subcutaneously (SC). In a recent clinical trial, participants received the standard 108 infectious units of vaccine SC or a one-fifth (IDH) or a one-tenth (IDL) dose ID twice 28-days apart. Two weeks after the second dose, sera were analyzed using a vaccinia virus (VACV) strain Western Reserve plaque-reduction test (PRNT) with the conclusion that IDH but not IDL was non-inferior to SC. The present study extends the latter by quantifying neutralizing antibodies to the MVA vaccine and to monkeypox virus (MPXV) in the absence and presence of added complement and by assessing multiplex binding antibodies to individual VACV antigens (A27, A33, B5, D8 and L1) and the MPXV homologs (A29, A35, B6, E8 and M1). The main conclusions of the study are that the titers of MVA neutralizing antibodies induced by SC and IDH were not significantly different, whereas MVA neutralizing antibody titers induced by IDL were lower like the previous PRNT results. However, the titers of complement-enhanced MPXV neutralizing antibodies induced by SC were significantly higher than for both IDH and IDL immunizations, suggesting that the standard SC dose and reduced dose ID immunizations may not be equivalent. Additional analyses suggested that antibody binding to VACV B5 and D8 and MPXV B6 and E8 may serve as surrogates for neutralizing antibodies.

Abstract Background Monkeypox (Mpox) is a global public health threat. In the current Democratic Republic of Congo (DRC) mpox outbreak, children < 15 years of age comprise 70% of cases and 88% of deaths. Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine is a live attenuated, non-replicating orthopoxvirus vaccine licensed in the US to prevent smallpox and mpox. MVA-BN is not approved in persons < 18 years of age (though is available in some countries under emergency use authorization). Geometric Mean Titers of Vaccinia-Specific PRNT by Time Point and Age Group Methods We conducted a Phase 2, open-label, multisite clinical trial to evaluate the safety and immunogenicity of two 1x108 TCID50 doses of MVA-BN vaccine administered subcutaneously 28 days apart in adolescents aged 12-17 years compared to adults aged 18-50 years (NCT05740982). A planned interim analysis evaluated safety through Day 210 (180 days post dose 2) and immunogenicity through Day 43 (14 days post dose 2). Results Three hundred fifteen adolescents (161 [51%] aged 12-14 years, 160 [51%] male, 216 [69%] white, 251 [80%] not Hispanic or Latino) were compared to 211 adults (94 [45%] male, 145 [69%] white, 149 [71%] not Hispanic or Latino). Solicited systemic and local events, and unsolicited adverse events (AEs), were similar in both groups. Dizziness was more common in adolescents (9 events in 8/315 (3%) versus none in adults) but similar to rates reported after other adolescent vaccines. Overall, MVA-BN was well tolerated. Day 43 antibody responses, based on vaccinia virus (Western Reserve strain) plaque-reduction neutralization titer (PRNT) assay geometric mean titer (GMT), elicited by MVA-BN in adolescents (470.3 [95% CI: 422.3, 523.8]) were non-inferior to the response in adults (293.2 [95% CI: 249.8, 344.2]); GMT ratio: 1.60 [95% CI: 1.32, 1.95]) (Figure). Conclusion The interim data demonstrate MVA-BN vaccine is well-tolerated and the peak GMT met prespecified non-inferiority criteria for adolescents as compared to adults. These findings are relevant to adolescents in the US and in areas where Mpox is endemic. Evaluations in younger children are urgently needed to extend protection to those who are most vulnerable. Disclosures C. Mary Healy, MD, FIDSA, Dexcom Inc: Stocks/Bonds (Public Company)|Hillevax, Inc: Member of Advisory board|Intuitive Surgical Inc: Stocks/Bonds (Public Company)|Quidel Corporation: Stocks/Bonds (Public Company)|Vapotherm: Stocks/Bonds (Public Company) C. Buddy Creech, MD, MPH, CommenseBio: Advisor/Consultant|GSK: Advisor/Consultant|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|TDCowen: Advisor/Consultant|UpToDate: Honoraria|Vedanta: Grant/Research Support Sharon E. Frey, MD, Bavarian Nordic: Grant/Research Support|Saint Louis University (SLU): Grant/Research Support

Introduction: Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine is being used to mitigate disease in the current global mpox outbreak, but a global vaccine shortage may limit large scale vaccination.Methods: Participants were randomized 1:1:1 to receive two doses of MVA-BN administered 28 days apart: intradermal (ID) 2 × 107 TCID50 (2 × 107 ID), ID 1 × 107 TCID50 (1 × 107 ID), or standard dose subcutaneous (SC) 1 × 108 TCID50 (1 × 108 ID). The primary objective was non-inferiority testing of each ID regimen compared to the standard SC regimen using vaccinia virus plaque reduction neutralizing titer assay (PRNT) geometric mean titers (GMT) at Day 43 (2 weeks post-second vaccination). Secondary objectives were non-inferiority testing of individual peak humoral immune responses, comparison of humoral immune responses, vaccinia virus-specific PRNT half-life (t½), and safety.Results: Day 43 non-inferiority by PRNT GMT was established for the 2 × 107 ID regimen but not the 1 × 107 ID regimen. The 2 × 107 ID regimen was also non-inferior to the SC dose at Days 15 and 29, prior to the second dose; the 1 × 107 ID regimen did not meet the non-inferiority criteria at any point post-vaccination. The three study regimens had similarly high seroconversion rates and similar anti-vaccinia PRNT half-lives.Most participants experienced injection site and systemic reactogenicity of moderate severity or less and only mild unsolicited adverse events (mostly skin discoloration and nodules at the injection site).Conclusion: The 2 × 107 ID regimen, but not the 1 × 107 ID regimen, was non-inferior to the SC regimen on Day 43. The study supports use of the 2 × 107 ID regimen if needed.Clinicaltrials.gov NCT05512949

BACKGROUND:Covid-19 vaccines are updated to match circulating strains based on reasoning that better strain-matched immunogenicity should provide better protection. Randomized evidence with disease endpoints to support strain matching is lacking. We evaluated COVID-19 incidence among adults randomized to a second booster of Prototype or Omicron-based vaccines. METHODS:COVAIL was a four-stage Phase 2 clinical trial; results from Stages 1 (mRNA-1273 [Moderna]) and 2 (BNT162b2 [Pfizer/BioNTech]) are described here. Adults who had received a primary series and one booster of an authorized COVID-19 vaccine were eligible. Participants received one dose of either Prototype vaccine or a monovalent or bivalent Omicron BA.1 vaccine. SARS-CoV-2 neutralization titers (ID50) were measured pre- and post-vaccination. Covariate-adjusted cumulative COVID-19 incidence and Cox regression analyses were conducted separately for each stage. RESULTS:706 participants with pre- and day 15 post-vaccination ID50 titers (n = 503 in Stage 1, n = 203 in Stage 2) were included. Within stages, participant characteristics and baseline ID50 titers were similar between Prototype and Omicron-based arms. There was no difference in cumulative COVID-19 incidence for Prototype vs. Omicron-based vaccine in Stage 1 (RR 1.04, 95 % CI 0.73-1.48), while incidence was higher among Prototype recipients in Stage 2 (RR 2.56, 1.44-4.52). Cox regression analysis showed no difference in Stage 1 (HR 1.04, 0.68-1.58), but higher incidence for Prototype recipients in Stage 2 (HR 2.95, 1.52-5.72). CONCLUSIONS:Omicron-based vaccines as second boosters were more protective against COVID-19 relative to Prototype among those receiving BNT162b2 but not mRNA-1273. Differences between stages such as force of infection, antigen matching, and vaccine differences may explain this finding. CLINICALTRIALS:govRegistry Number: NCT05289037.

While at least 8 monoclonal and 3 polyclonal antibody products have been tested in clinical trials for the treatment of influenza, no products have been licensed, and most have stopped clinical development. The COVID-19 pandemic demonstrated that these approaches, especially monoclonal antibodies, may have unique potential in certain stages of disease and populations, especially in preventing severe disease in a population without preexisting immunity or in those with a limited capacity to mount an effective humoral immune response. This review summarizes past and ongoing efforts in using monoclonal and polyclonal antibodies for the treatment and prevention of influenza, focusing on products that have entered clinical trials and drawing lessons from COVID-19 to direct future efforts on these strategies.

BACKGROUND:Mucosal immunity plays a critical role in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and replication. Understanding the capacity of coronavirus disease 2019 (COVID-19) vaccines to elicit both mucosal and systemic antibodies could help optimize vaccination strategies. METHODS:We conducted an open-label, phase 1/2 adaptive-design clinical trial to evaluate the safety and immunogenicity of COVID-19 immunizations. Healthy adults received 2 priming doses of mRNA-1273, a booster dose of mRNA-1273, and a second booster of bivalent (WA-1 and BA.4/BA.5) mRNA-1273.222. Adverse event data were collected. Serum and mucosal immunity were evaluated. RESULTS:One hundred six persons were enrolled. Thirty received all 4 study-related vaccine doses. All vaccines were well tolerated, with injection site pain, malaise, myalgias, and headache being the most frequently reported symptoms. Among those who received a second booster, 24 of 30 (80%) had serological evidence of SARS-CoV-2 infection. Following the second booster, increases in geometric mean binding and pseudovirus neutralization antibody titers to the ancestral strain and BA.1 and BA.5 variants were observed. Increases in mucosal immunoglobulin G and immunoglobulin A (IgA) antibodies in nasal and salivary samples were observed in both previously infected and infection-naive participants, although prior infection markedly boosted virus-specific mucosal IgA responses. CONCLUSIONS:The mRNA-1273.222 booster vaccine was safe and immunogenic and induced mucosal antibody responses in previously infected and infection-naive persons. CLINICAL TRIALS REGISTRATION:NCT04889209.

BACKGROUND:Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS:Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS:Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS:Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy. CLINICAL TRIAL REGISTRATION:NCT04280705 (ClinicalTrials.gov).

Objectives Influenza-like illness (ILI) caused by respiratory viruses results in various respiratory clinical manifestations. The ILI002 prospective observational cohort study aimed to describe viral agents, seasonality, and outcomes of patients with ILI during four seasons in the influenza H1N1-pandemic and post-pandemic years (2010-2014). Methods Patients from six Mexican hospitals were enrolled from April 2010 to March 2014. Clinical data and nasopharyngeal swabs were obtained and tested for viral respiratory pathogens by real-time reverse-transcription polymerase chain reaction. Results Of the 5662 enrolled participants, 64.9% were adults and 35.1% were children. Among the 5629 participants with single-pathogen detection, rhinovirus (20.2%), influenza virus (11.2%), respiratory syncytial virus (RSV) (7.2%), and coronavirus (6.8%) were the most frequent pathogens. Co-infection occurred in 14.5% of cases; 49.3% of participants required hospitalization, particularly in RSV cases (42.9% adults, 89.6% children). The mortality rate was 2.8% higher among older adult participants and those with comorbidities. Influenza H1N1 had the highest mortality rate, yet almost half of the deceased had no pathogen. Rhinovirus persisted year-round, while influenza, coronavirus, and RSV peaked during cooler months. Conclusions Analyses showed that some viruses causing ILI may lead to severe disease and hospitalization irrespective of comorbidities. These findings may help in decision-making about public health policies on prevention measures, vaccination, treatment, and administration of health care.

The emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses and their transmission to dairy cattle and animals, including humans, poses a major global public health threat. Therefore, the development of effective vaccines and therapeutics against H5N1 clade 2.3.4.4b virus is considered a public health priority. In the United States, three H5N1 vaccines derived from earlier strains of HPAI H5N1 (A/Vietnam, clade 1, and A/Indonesia, clade 2.1) virus, with (MF59 or AS03) or without adjuvants, are licensed and stockpiled for pre-pandemic preparedness, but whether they can elicit neutralizing antibodies against circulating H5N1 clade 2.3.4.4b viruses is unknown. In this study, we evaluated the binding, hemagglutination inhibition and neutralizing antibody response generated after vaccination of adults with the three licensed vaccines. Individuals vaccinated with the two adjuvanted licensed H5N1 vaccines generated cross-reactive binding and cross-neutralizing antibodies against the HPAI clade 2.3.4.4b A/Astrakhan/3212/2020 virus. Seroconversion rates of 60-95% against H5 clade 2.3.4.4b were observed after two doses of AS03-adjuvanted-A/Indonesia or three doses of MF59-adjuvanted-A/Vietnam vaccine. These findings suggest that the stockpiled US-licensed adjuvanted H5N1 vaccines generate cross-neutralizing antibodies against circulating HPAI H5N1 clade 2.3.4.4b in humans and may be useful as bridging vaccines until updated H5N1 vaccines become available. Avian influenza vaccines in the US strategic stockpile elicit immune responses that recognize the clade of avian influenza circulating in cows and could be a resource before newer vaccines are approved and deployed.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Local Reaction to Mpox Vaccine In a trial of mpox vaccine, intradermal administration led to more erythema and induration than the subcutaneous route but resulted in a similar level of immune response with 20% of the dose.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.

BACKGROUNDAntibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT 006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalized with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A.METHODSTo probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalized with influenza A or B viruses (IAV or IBV) were analyzed for antibody isotype/subclass and Fcγ receptor (FcγR) binding by ELISA, bead-based multiplex, and NK cell activation assays.RESULTSInfluenza-specific FcγR-binding antibodies were elevated in Flu-IVIG-infused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcγR binding were associated with more favorable outcomes. Flu-IVIG therapy also improved the odds of a more favorable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcγR-binding antibody was associated with less favorable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favorable outcome in participants with low levels of anti-IAV Fc-functional antibody.CONCLUSIONThese detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies.TRIAL REGISTRATIONClinicalTrials.gov NCT02287467.FUNDINGFunding for this research was provided by subcontract 13XS134 under Leidos Biomedical Research Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent SARS-CoV-2 mRNA vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wildtype spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Vaccine protection against COVID-19 wanes over time and has been impacted by the emergence of new variants with increasing escape of neutralization. The COVID-19 Variant Immunologic Landscape (COVAIL) randomized clinical trial (clinicaltrials.gov NCT05289037) compares the breadth, magnitude and durability of antibody responses induced by a second COVID-19 vaccine boost with mRNA (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2), or adjuvanted recombinant protein (Sanofi CoV2 preS DTM-AS03) monovalent or bivalent vaccine candidates targeting ancestral and variant SARS-CoV-2 spike antigens (Beta, Delta and Omicron BA.1). We found that boosting with a variant strain is not associated with loss in neutralization against the ancestral strain. However, while variant vaccines compared to the prototype/wildtype vaccines demonstrated higher neutralizing activity against Omicron BA.1 and BA.4/5 subvariants for up to 3 months after vaccination, neutralizing activity was lower for more recent Omicron subvariants. Our study, incorporating both antigenic distances and serologic landscapes, can provide a framework for objectively guiding decisions for future vaccine updates.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 .

Background Human Bocaviruses (HBoV) can cause acute respiratory tract infections. High coinfection rates cloud its pathogenicity. This study sought to describe the clinical features of HBoV1 disease in children and adults with Influenza-like illness (ILI), exploring associations between viral load, clinical features, and seasonality.Methods Patients who tested positive for HBoV1 by polymerase chain reaction, enrolled from April 2010 to March 2014 in the ILI002 prospective observational cohort study were included in this cross-sectional nested study. Participants were included in ILI002 if they presented with signs and/or symptoms suggestive of influenza-like illness. Samples were tested for viral load, and NP1 and VP1/VP2 phylogenetic analyses, except for the samples lacking suitable and viable clinical material for genotyping.Findings We identified HBoV1 in 157 (2.8%) of participants. Prevalence was 4.5% in children and 1.8% in adults. Single HBoV1 detection occurred in 41.1% and 46.3% of children and adults, respectively. Children commonly experienced fever (83.3%), cough with sputum (74.4%), and shortness of breath (72.2%). In the multivariate analysis of children, significant positive associations were detected between viral loads and age (0.20 [95% CI: 0.07, 0.33]), and the presence of fever (2.64 [95% CI: 1.35, 3.94]), nasal congestion (1.03 [95% CI: 0.07, 1.99]), dry cough (1.32 [95% CI: 0.42, 2.22]), chest congestion (1.57 [95% CI: 0.33, 2.80]), red eyes (1.25 [95% CI: 0.35, 2.14]), cough with sputum (1.79 [95% CI: 0.80, 2.78]), and other signs and symptoms such as chills, dizziness, and diaphoresis (1.73 [95% CI: 0.19, 3.27]). In contrast, significant negative associations were found between viral loads and percent neutrophils on the blood count (-0.04 [95% CI: -0.06,-0.02]), fatigue (-1.60 [95% CI: -2.46,-0.74]) and the presence of other symptoms or signs, including adenopathy and rash (-1.26 [95% CI: -2.31,-0.21]). Adults commonly experienced sore throat (73.1%), fatigue (77.4%), and headache (73.1%). In the multivariate analysis of adults, significant positive associations were detected between viral load and body mass index (0.13 [95% CI: 0.04, 0.21]), and the presence of confusion (1.54 [95% CI: 0.55, 2.53]), and sore throat (1.03 [95% CI: 0.20, 1.85]), and significant negative associations were detected between viral load and chest congestion (-1.16 [95% CI: -2.07,-0.24]). HBoV1 was detected throughout the year irrespective of season, temperature, and humidity. The Health 2024;29: Published https://doi.org/10. 1016/j.lana.2023. 100647