Unsolicited Adverse Events Research Articles

A double-blind, randomised phase III clinical trial to evaluate safety, immunogenicity, non-inferiority & lot to lot consistency of single component oral cholera vaccine BBV131 (Hillchol®) in comparison to Shanchol™.

A double-blind, randomised phase III clinical trial to evaluate safety, immunogenicity, non-inferiority & lot to lot consistency of single component oral cholera vaccine BBV131 (Hillchol®) in comparison to Shanchol™.

Safety and immunogenicity of a bivalent Ebola virus and Sudanvirus ChAdOx1 vectored vaccine in adults in the UK: anopen-label, non-randomised, first-in-human, phase 1 clinicaltrial.

Four Orthoebolavirus species can cause Ebola disease, with Ebola virus (species Orthoebolavirus zairense) and Sudan virus (species Orthoebolavirus sudanense) responsible for the majority of outbreaks and cases. No vaccines have been approved against orthoebolaviruses other than Ebola virus. We aimed to evaluate the safety and immunogenicity of a non-replicating single-adenoviral vaccine (ChAdOx1 biEBOV) encoding both Ebola virus and Sudan virus glycoproteins. In this open-label, non-randomised, first-in-human, phase 1, dose-escalation clinical trial of ChAdOx1 biEBOV, participants aged 18-55years without clinically significant medical comorbidities or previous adenovirus vaccine exposure were recruited at a single site (Oxford, UK). Participants were non-randomly enrolled to a low-dose group (5 × 10⁹ viral particles [vp] of ChAdOx1 biEBOV), a medium-dose group (2·5 × 101⁰ vp), and a high-dose group (5 × 101⁰ vp). All doses were administered intramuscularly. After recruitment of all participants, the protocol was amended so that a subgroup from the high-dose group received a second high dose of vaccine 12weeks after the first dose. Primary outcome measures were assessment of solicited adverse events for 7days after vaccinations, unsolicited adverse events for 28days after vaccinations, changes in clinical laboratory measures within 28days after vaccination, and serious adverse events and adverse events of special interest for the study duration. Secondary outcomes were assessment of humoral and cellular immunity to Ebola virus and Sudan virus glycoprotein. This study is registered with ClinicalTrials.gov, NCT05079750. Between Nov 11, 2021, and April 7, 2022, 40individuals attended the trial screening visit, of whom 26were enrolled (six in the low-dose group, six in the medium-dose group, and 14in the high-dose group). Seven participants in the high-dose group received one vaccine dose and seven received two vaccine doses. Local solicited adverse events were reported by 17 (65%) of 26participants after dose 1and five (71%) of seven after dose 2. Systemic solicited adverse events were reported by 23 (88%) participants after dose 1and five (71%) after dose 2. All solicited adverse events were mild or moderate, with no severe events reported. No serious adverse reactions were reported. Unsolicited adverse events related to vaccination were mostly mild or moderate and short-lived, such as joint pain or upper respiratory symptoms. One adverse event of special interest, thrombocytopenia, occurred transiently in one participant in the high-dose group. Rapidly resolving lymphopenia was common at the early post-vaccination timepoint. Asingle 5 × 101⁰ vp dose vaccination elicited seropositivity to Ebola virus in 14 (100%) participants in the high-dose group and elicited seropositivity to Sudan virus in 12 (86%) participants in the high-dose group; antibody titres were boosted in the two-dose group. Our results suggest that the ChAdOx1 biEBOV vaccine was safe and well tolerated. Safety and tolerability data are consistent with other vaccines using the same vaccine backbone. Asingle 5 × 101⁰ vp dose of the vaccine was immunogenic, generating binding antibodies against both Ebola virus and Sudan virus glycoproteins, with antibody responses boosted in the subgroup receiving a second immunisation. Future research should focus on approaches to enhance antibody responses and to elicit neutralising antibodies to Sudan virus. UK Research and Innovation.

High Frequency of Chronic Urticaria Following an Investigational HIV-1 BG505 MD39.3 Trimer mRNA Vaccine in a Phase 1, Randomized, Open-Label Clinical Trial (HVTN 302).

The mRNA platform is under investigation for many vaccines, including HIV-1 vaccines. To evaluate the safety and tolerability of 3 investigational HIV-1 trimer mRNA vaccines. Safety analysis of mRNA vaccination in a phase 1, randomized, open-label trial. (ClinicalTrials.gov: NCT05217641). Ten research sites in the United States. 108 volunteers aged 18 to 55 years without HIV-1. Investigational HIV-1 BG505 MD39.3 trimer mRNA vaccines (gp140 soluble trimer, gp151 membrane-bound trimer, and gp151 CD4KO membrane-bound trimer) at doses of 100 and 250 mcg at 0, 2, and 6 months. Solicited and unsolicited adverse reactions and events reported during the 12 months after the first vaccination. Participants (n = 108) were randomly assigned to 6 vaccine groups. Mild to moderate local and systemic solicited events were common. Eighty participants reported 190 unsolicited adverse events (AEs); 30 were considered to be related to a study product. Most (73%) related AEs were mild, and the rest were moderate. Among related AEs, urticaria was reported by 7 of 108 participants (7% [95% CI, 3% to 13%]), 4 of whom had unresolved, intermittent urticaria at 12 months. In post hoc analyses, demographic characteristics, history of allergy or medication use, and COVID-19 were not associated with urticaria. In a comparison of participants with versus without urticaria, 100% (7 of 7; CI, 65% to 100%) versus 37% (37 of 101; CI, 28% to 46%) reported previous Moderna COVID-19 vaccination, 29% (2 of 7; CI, 8% to 64%) versus 76% (77 of 101; CI, 67% to 84%) reported previous Pfizer-BioNTech COVID-19 vaccination, and 0% (0 of 7; CI, 0% to 35%) versus 5% (5 of 101; CI, 2% to 11%) reported no previous mRNA COVID-19 vaccination. Lack of a placebo group, open-label study, and post hoc evaluation of urticarial risk. Urticarial reactions associated with experimental HIV-1 mRNA vaccines were observed in this trial. Studies to investigate the mechanism and approaches to mitigate these reactions are underway to further advance HIV-1 vaccine research. National Institutes of Health, National Institute of Allergy and Infectious Diseases.

Effect of Tadalafil on cardiac function and left ventricular dimensions in Duchenne muscular dystrophy: safety and cardiac MRI substudy results from a randomized, placebo-controlled trial

BackgroundInhibition of phosphodiesterase 5 (PDE5) was hypothesized to slow disease progression in Duchenne muscular dystrophy (DMD). Tadalafil, a once-daily PDE5 inhibitor, did not slow loss of ambulation in a phase 3 placebo-controlled trial. This report details the cardiac findings from this study.MethodsPatients with DMD (N = 331) aged 7 to 14 years on stable glucocorticoids were randomized to tadalafil 0.3 mg/kg/day, 0.6 mg/kg/day, or placebo. Ejection fraction (EF), fractional shortening, and M-mode ventricular dimensions were measured on echocardiograms. 12-lead ECGs were centrally evaluated for heart rate and intervals, and qualitative diagnoses. Vital signs and unsolicited adverse events were collected throughout the study. Cardiac MRI (CMR) was collected in a subset of 27 patients. Z-scores for ventricular dimensions and volumes were calculated based on published age-normative reference values. Treatment differences for change in continuous ECG parameters and vital signs were compared using Wilcoxon rank-sum tests. Echocardiogram and CMR parameters were analyzed with an ANCOVA model.ResultsTadalafil had no adverse effects on echocardiographic left ventricular (LV) EF or fractional shortening, ECG findings, or vital signs. Mean diastolic LV internal dimension (LVIDd) was increased in the tadalafil 0.6 mg/kg group versus placebo at Week 24 (+ 0.13 cm, p =.019) and Week 48 (+ 0.18 cm, p =.008), with a similar pattern observed for LV systolic dimensions (LVIDs). Mean LV end diastolic volume (EDV) measured by CMR also increased at Week 48 in the tadalafil 0.3 mg/kg (+ 13.0 ml, p =.047 vs. placebo) and 0.6 mg/kg (+ 12.0 ml, p =.08 vs. placebo) groups, with numerically smaller increases in LV EDV and commensurate increases in stroke volume and cardiac output. Z-scores for LVIDd and LV EDV were generally below the normal range at baseline and increased toward or within the normal range in the tadalafil groups but not in the placebo group.ConclusionsNo adverse effects of tadalafil on cardiovascular function were evident based on adverse events, echocardiograms, ECG, or vital sign measurements through 48 weeks in patients with DMD. The small mean increases in LVID and LV volume observed with tadalafil are consistent with PDE5 inhibitor pharmacology, but their clinical relevance in the context of LV tonic contraction in DMD is unknown and deserve further study.ClinicalTrials.gov identifierNCT01865084 (first registration date: 24-May-2013).

Immunogenicity and safety of different immunisation schedules of the VLA15 Lyme borreliosis vaccine candidate in adults, adolescents, and children: a randomised, observer-blind, placebo-controlled, phase 2 trial.

Immunogenicity and safety of different immunisation schedules of the VLA15 Lyme borreliosis vaccine candidate in adults, adolescents, and children: a randomised, observer-blind, placebo-controlled, phase 2 trial.

Live-attenuated Mycobacterium tuberculosis vaccine, MTBVAC, in adults with or without M tuberculosis sensitisation: a single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial.

Live-attenuated Mycobacterium tuberculosis vaccine, MTBVAC, in adults with or without M tuberculosis sensitisation: a single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial.

Immunogenicity of inactivated quadrivalent influenza vaccine in pregnant women, including the level of postvaccination antibodies in umbilical cord blood.

Immunogenicity of inactivated quadrivalent influenza vaccine in pregnant women, including the level of postvaccination antibodies in umbilical cord blood.

Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting.

Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Results of a randomized vaccine-controlled phase I ADAPTCOV trial in Brazil.

Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Results of a randomized vaccine-controlled phase I ADAPTCOV trial in Brazil.

MRNA-based seasonal influenza and SARS-CoV-2 multicomponent vaccine in healthy adults: a phase 1/2 trial.

A multicomponent vaccine targeting several seasonal respiratory pathogens may provide simultaneous protection in a single-injection regimen. We present interim (28 days) findings from a phase 1/2 study of an mRNA-based multicomponent vaccine (mRNA-1083), encoding seasonal influenza and SARS-CoV-2 antigens. Adults (18-79 years) were randomly assigned to receive different compositions of mRNA-1083 at varying dose levels on day 1. The primary study objectives were reactogenicity through 7 days and safety through 28 days postvaccination, and the secondary study objective was immunogenicity against vaccine-matched influenza and SARS-CoV-2 strains at day 29 assessed by hemagglutination inhibition and pseudovirus neutralization assays, respectively. The multicomponent mRNA-1083 vaccine was generally well-tolerated, with most solicited adverse reactions being Grade 1 or 2 in severity. The incidence of unsolicited adverse events was similar across vaccine groups. mRNA-1083 induced immune responses against influenza and SARS-CoV-2 that were, in general, similar to or higher than those achieved with licensed quadrivalent influenza (standard or high dose) and SARS-CoV-2 (bivalent mRNA-1273) vaccines. These data support ongoing phase 3 evaluation of the mRNA-1083 vaccine. ClinicalTrials.gov registration: NCT05827926 .

Safety, tolerability and immunogenicity of a condensed, multi-dose prime regimen of PfSPZ Vaccine for the prevention of Plasmodium falciparum malaria infection

BackgroundThe World Health Organization (WHO) has called for new malaria vaccines with > 90% efficacy against Plasmodium falciparum infection to expand the anti-disease benefit provided by the RTS,S/AS01 and R21/Matrix M subunit vaccines currently administered to infants and young children in sub-Saharan Africa. Attenuated P. falciparum sporozoites (PfSPZ) are being developed as a traveller’s vaccine and to fulfill WHO’s call for high-level efficacy in endemic countries to support malaria elimination.MethodsPfSPZ Vaccine, comprised of radiation-attenuated PfSPZ, was compared with normal saline placebo in a randomized, double-blind trial targeting 60 malaria-naive US adults to assess safety, tolerability, immunogenicity, and efficacy against heterologous controlled human malaria infection three and twelve weeks after immunization. Pharmacists provided syringes to blinded clinicians using 3:1 (vaccine:placebo) blocked randomization, for administration by direct venous inoculation on days 1 and 8 (multidose prime) and day 29 (boost), a condensed regimen with superior efficacy. Primary outcomes included adverse events and antibody responses to the P. falciparum circumsporozoite protein (PfCSP).Results31 participants were screened, randomized and immunized twice (V1, V2) 5–7 days apart, with one withdrawal after an intercurrent adverse event. A vial issue, later traced to the vial manufacturer, halted further immunizations. Solicited local and systemic adverse events recorded for 2 and 7 days after immunizations, respectively, occurred with equal frequency and severity in the 23 vaccinees and 7 controls receiving two immunizations, as did unsolicited adverse events recorded for 28 days and laboratory abnormalities 1 and 5 weeks after V2. Four of 23 vaccinees and one of 7 controls (p = 1.00) developed grade 2 adverse events including subjective fever, headache, malaise, fatigue, rigors, arthralgia and myalgia after V2 but not V1, these symptoms generally resolving within 24 h. Twenty-two of 23 (96%) vaccinees developed IgG (median 99-fold increase over baseline) and IgM (median 1,110-fold increase) antibodies to PfCSP one week after V2. Antibody responses were not associated with reactogenicity.ConclusionsThe two-dose priming immunization regimen was safe, well tolerated and highly immunogenic. Larger studies may better define the adverse event profile of condensed regimens of PfSPZ Vaccine in malaria-naive adults.Trial registration number: clinicaltrial.gov NCT05604521.

Immune response and safety of the adjuvanted recombinant zoster vaccine in adults 50years of age and older in India: A randomized phase 3 trial.

Reactivation of latent varicella-zoster virus can cause herpes zoster (shingles) and associated complications, such as post-herpetic neuralgia. The adjuvanted recombinant zoster vaccine (RZV) was shown to be efficacious in preventing herpes zoster and have an acceptable safety profile in adults ≥50years of age. However, no clinical data on RZV were available in an Indian population. The aim of the current study was to assess the immunogenicity and safety of RZV in adults ≥50years of age in India. In this randomized, placebo-controlled, observer-blind, multi-center trial, conducted between February 2022 and March 2023, participants ≥50years of age received two doses (with a two-month interval) of RZV (N=143) or placebo (N=145). Blood samples were collected pre-dose 1 and one month post-dose 2 to quantify anti-glycoprotein E (gE) antibody concentrations. Solicited adverse events (AEs) with onset within seven days and unsolicited AEs with onset within 30days following any RZV or placebo dose were recorded. Serious AEs (SAEs) and potential immune-mediated diseases (pIMDs) were recorded until trial end (six months post-dose 2). At one month post-dose 2, vaccine response rate in the RZV group was 85.7% (95% confidence interval [CI]: 78.4%-91.3%), meeting the primary objective's success criterion (lower limit of 95% CI ≥60%). The adjusted geometric mean anti-gE antibody concentration ratio between the RZV and placebo groups was 19.8 (95% CI, 14.1-27.8), meeting the secondary objective's success criterion (lower limit of 95% CI ≥3). Solicited AEs were reported by 103 (72.0%) RZV and 86 (59.3%) placebo recipients; most had mild-to-moderate severity. No intervention-related unsolicited AE or SAE and no pIMD or death were reported. Two doses of RZV induced a robust antibody response, comparable to that reported in other populations, and had a safety profile similar to the known RZV safety profile. gov: NCT05219253.

Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adults.

Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adults.

Safety comparison between Pfizer BNT162b2, Moderna mRNA-1273, and AstraZeneca AZD1222 in a Nationwide prospective cohort survey at the beginning of the severe acute respiratory syndrome coronavirus 2 vaccination in Japan.

This study was conducted at 112 government and Juntendo University hospitals in February 2021 for the primary series of SARS-CoV-2 vaccinations. We compared the timing of solicited adverse event (AE) onset and prevalence of unsolicited AEs for Pfizer, Moderna, and AstraZeneca vaccines in a nationwide, large-scale prospective cohort study. The Pfizer and Moderna mRNA vaccines were associated with a higher frequency of fever after the second dose than after the first dose. The AstraZeneca viral vector vaccine resulted in more frequent side effects after the first dose. The side effects of mRNA vaccines were the most common on the day after vaccination and almost subsided by the fourth day. The incidence of systemic AEs, including fever of ≥37.5°C, was the highest for Moderna, followed by AstraZeneca and Pfizer. Local reactions were less frequent with the AstraZeneca vaccine than with the Pfizer and Moderna vaccines but tended to last longer. The frequency of AEs was higher in women than in men. The odds ratio for age per year regarding systemic reactions (adjusted for sex) was the least for AstraZeneca, followed by Pfizer and Moderna (< 1), indicating a more pronounced decrease in the frequency of fever and systemic reactions with increasing age. Age effects varied among vaccines. Delayed skin reactions, appearing around the seventh day after the first dose (Day 8), were observed as itchy redness, particularly in women aged ≥30 with the Moderna vaccine and less often with the Pfizer vaccine. Over half of the delayed skin reactions involved local erythema immediately after the second dose, but these reactions mostly disappeared within approximately 10days. Despite differences in the incidence of AEs among the three vaccines by age and sex, all vaccines were well-tolerated. These findings provide crucial safety information, supporting informed vaccination decisions and ongoing surveillance efforts.

Efficacy safety of chemoprophylactic plasmodium falciparum and sporozoite vaccines for malaria prevention: a systematic review and meta- analysis

PfSPZ-CVac, an innovative vaccine, aims to combat malaria by using live, weakened Plasmodium falciparum sporozoites in combination with chloroquine. This approach employs the whole parasite, triggering a strong immune response and potentially providing long-term protection. The objective of this study is to assess the efficacy and safety of the PfSPZ- Chemoprophylaxis Vaccine (PfSPZ-CVac) for malaria prevention. A systematic review following PRISMA guidelines was conducted, focusing on randomized controlled trials (RCTs) that assessed the efficacy and safety of the vaccine. Seven eligible studies were selected from eight electronic databases. The quality was assessed using the Cochrane Risk of Bias tool, and data analysis was performed using Review Manager 5.4. PfSPZ-CVac combines live sporozoites with chloroquine, which prevents the parasite from entering the liver and enhance the body’s immune response, particularly T-cell activation, to provide long- lasting protection against malaria. The meta-analysis revealed a significant reduction in parasitemia (P&lt;0.00001, I²=35%, MD=0.38). Local solicited adverse events did not show a significant increase (MD=0.73, P=0.45, I²=0%). Similarly, systemic solicited adverse events and unsolicited adverse events demonstrated minimal risks (MD=0.89, P=0.56, I²=23%; MD=0.65, P=0.20, I²=0%). Although PfSPZ-CVac exhibits high efficacy, its administration is complex, and it carries a slight of rare adverse reactions. PfSPZ-CVac demonstrates potential for providing strong, long-term protection against malaria , with a positive safety profile, making it a promising candidate for widespread use in high-transmission regions.

Safety and immunogenicity of a single-dose omicron-containing COVID-19 vaccination in adolescents: an open-label, single-arm, phase 2/3 trial

Safety and immunogenicity of a single-dose omicron-containing COVID-19 vaccination in adolescents: an open-label, single-arm, phase 2/3 trial

Safety and immunogenicity of Omicron protein vaccines in mRNA-vaccinated adolescents: A phase 3, randomised trial.

Safety and immunogenicity of Omicron protein vaccines in mRNA-vaccinated adolescents: A phase 3, randomised trial.

P-601. Safety and Immunogenicity of a Respiratory Syncytial Virus and Human Metapneumovirus Virus-like Particle Protein Subunit Combination Vaccine in 60–85-Year-Old Adults: Interim Results from a Phase 2a Clinical Trial

BackgroundRespiratory syncytial virus (RSV) and human metapneumovirus (hMPV) often cause serious lower respiratory tract infections in older adults. In this phase 2a trial, we evaluate the safety and immunogenicity of an RSV/hMPV virus-like particle (VLP) subunit combination vaccine, IVX-A12, ± adjuvant in 60–85-year-olds (NCT05903183). We present interim data to Day 180 post vaccination.Figure.Geometric mean titers (GMTs) against RSV-A, RSV-B, hMPV-A, and hMPV-B at baseline and Days 28 and 180 post vaccinationMethodsParticipants were randomized 2:2:1 to receive a single dose of IVX-A12 containing 150µg RSV/150µg hMPV ± MF59® (CSL Seqirus) oil-in-water adjuvant, or placebo. Safety assessments included solicited and unsolicited adverse events (AEs), serious AEs (SAEs), AEs of special interest (AESIs), and medically attended AEs (MAAEs). Geometric mean titers (GMTs) of RSV and hMPV neutralizing antibodies are reported for Days 28 and 180.ResultsIn total, 264 participants were included (IVX-A12 n=103; IVX-A12+MF59 n=108; placebo n=53), with a median age of 69.2 years (range 60–85) and 57.6% were female. Solicited and unsolicited AEs were mostly mild with no related SAEs, AESIs, or MAAEs. For IVX-A12, GMTs (international units/mL) against RSV-A and B were 2078 (95% CI: 1628, 2653) and 1507 (1180, 1926) at baseline, 12171 (9680, 15303) and 5533 (4360, 7020) at Day 28, and 7216 (5706, 9124) and 3277 (2627, 4089) at Day 180, respectively (Figure). For IVX-A12+MF59, GMTs were 2482 (2003, 3075) and 1465 (1175, 1827) at baseline, 12643 (9829, 16263) and 4536 (3623, 5680) at Day 28, and 7967 (6219, 10206) and 2836 (2281, 3526) at Day 180, respectively.For IVX-A12, GMTs (assay units/mL) against hMPV-A and B were 498 (412, 601) and 6322 (4841, 8255) at baseline, 1568 (95% CI 1242, 1980) and 15337 (12371, 19013) at Day 28, and 655 (550, 781) and 9795 (7788, 12319) at Day 180, respectively. For IVX-A12+MF59, GMTs were 615 (501, 754) and 6160 (4828, 7859) at baseline, 1527 (1250, 1864) and 16673 (14284, 19461) at Day 28, and 711 (614, 823) and 8938 (7128, 11209) at Day 180.ConclusionIVX-A12 containing 150µg RSV/150µg hMPV was well tolerated and immunogenic against RSV and hMPV to 6 months in older adults up to 85 years of age, regardless of adjuvant. These data support the ongoing clinical development of an unadjuvanted RSV/hMPV VLP combination vaccine.DisclosuresMax Ciarlet, PhD, Icosavax/AstraZeneca: Employee of Icosavax, a member of the AstraZeneca Group, and may or may not hold stocks in AstraZeneca Elizabeth M Adams, MD, Icosavax/AstraZeneca: Employee of Icosavax, a member of the AstraZeneca Group, and may or may not hold stocks in AstraZeneca Nicholas Hourguettes, BA, Icosavax/AstraZeneca: Employee of Icosavax, a member of the AstraZeneca Group, and may or may not hold stocks in AstraZeneca Judy Wen, BA Econ, Icosavax/AstraZeneca: Employee of Icosavax, a member of the AstraZeneca Group, and may or may not hold stocks in AstraZeneca Wasima Rida, PhD, COH NCI grant for CMV vaccination of HCT-D: Grant/Research Support|Icosavax/AstraZeneca: Employee of Icosavax, a member of the AstraZeneca Group, and may or may not hold stocks in AstraZeneca Jennifer Price, BS, Icosavax/AstraZeneca: Employee of Icosavax, a member of the AstraZeneca Group, and may or may not hold stocks in AstraZeneca Lee-Jah Chang, MD, AstraZeneca: Employee of AstraZeneca Niranjan Kanesa-Thasan, MD, Icosavax/AstraZeneca: Previous employee of Icosavax, a member of the AstraZeneca Group

220. A Phase 2 Double-Blind, Placebo-Controlled Study Showing Oral Tableted Norovirus Vaccine VXA-G1.1-NN is Immunogenic, Efficacious, and Reduces Viral Shedding Following Norovirus Challenge

Abstract Background Norovirus (NV) is a leading cause of acute gastroenteritis worldwide. Currently no specific therapy exists for norovirus gastroenteritis (NVG). VXA-G1.1-NN is a nonreplicating adenovirus-vectored thermostable oral NV vaccine shown in clinical trials to be safe, well-tolerated and generates robust serum and mucosal immune responses. This study investigated safety, immunogenicity, and protective efficacy of VXA-G1.1-NN following NV GI.1 challenge.Figure 1.Clinical outcomes (norovirus infection and norovirus gastroenteritis) after norovirus challenge 28 days post vaccination with VXA-G1.1-NN or placebo Methods 165 healthy adults ages 18-49 were randomized 1:1 to a single oral vaccination of VXA-GI.1-NN or placebo. At 28 days post-vaccination, 141 eligible subjects were challenged with 1x106 genomic copies NV GI.1 inoculum. Solicited symptoms of reactogenicity were recorded for 1 week after vaccination and unsolicited adverse events (AEs) through 28 days post challenge. NVG was assessed by incidence of acute gastroenteritis (AGE) with evidence of NV+ infection. NV shedding was evaluated by qPCR in stool and emesis. VP1-specific GI.1 IgA antibody secreting cells (ASC), serum IgA and IgG, and Norovirus Blocking Antibody Assay (NBAA) were assessed. Totality of evidence analysis was used to assess overall vaccine protective effect.Figure 2.Viral shedding in stool by qPCR through 7 days post challenge with GI.1 NN virus inoculum following vaccination with VXA-G1.1-NN or placebo Results VXA-G1.1-NN was safe and well tolerated.VXA-G1.1-NN induced strong serum and cellular immunogenicity with substantial increases in VP1 GI.1- specific ASC and serum antibodies. Serum functional antibody responses, determined by NBAA, were significantly higher in subjects in the vaccine group compared to placebo. VP1 specific IgA was significantly increased in nasal secretions and saliva in the vaccine group. Protective efficacy for prevention of NVG was 21% (p= 0.149) and for NV infection was 29% (p= 0.003). An 85% decrease in geometric mean viral shedding in stool in the VXA-G1.1-NN group was also observed. Totality of evidence analysis for all 6 outcomes simultaneously provided a z-score of 5.56 (p&amp;lt; 0.001), indicating protective benefit of VXA-G1.1-NN.Figure 3.Cellular and serum immune responses following vaccination with VXA-G1.1-NN or placebo Conclusion VXA-G1.1-NN was safe, immunogenic, and reduced both viral shedding and NV infection following NV challenge. VXA-G1.1-NN tableted vaccine may help limit outbreaks by reducing viral shedding. Totality of evidence analysis for treatment effect provided a strong statistical signal supporting a protective effect of VXA-G1.1-NN. Disclosures Susan Greco, MD, MPH, Vaxart, Inc: Stocks/Bonds (Public Company) Becca A. Flitter, PhD, MPH, Vaxart Inc: Stocks/Bonds (Public Company) Lam Nguyen, MD, CVS Health: Stocks/Bonds (Public Company)|Vaxart: Author is either employed and/or has received stock options from Vaxart as part of this work.|Vaxart: Stocks/Bonds (Public Company) Darreann Carmela Hailey, MS, Bionano Genomics: Stocks/Bonds (Public Company)|Vaxart, Inc.: Stocks/Bonds (Public Company) Sean N. Tucker, PhD, Vaxart, Inc.: Grant/Research Support|Vaxart, Inc.: patent|Vaxart, Inc.: Ownership Interest|Vaxart, Inc.: Stocks/Bonds (Public Company) James F. Cummings, MD, VAXART: Stocks/Bonds (Public Company)

579. Safety and Immunogenicity of Mpox Vaccination in Adolescents

Abstract Background Monkeypox (Mpox) is a global public health threat. In the current Democratic Republic of Congo (DRC) mpox outbreak, children &amp;lt; 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 &amp;lt; 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