1049. Minimal Transient HIV-1 Viremia Following Vaccination Regimens Containing AD26. ZEBOV and MVA-BN-Filo in ART-Suppressed People Living with HIV

Background Ebola Virus Disease (EVD) outbreaks primarily occur in the HIV endemic setting of Sub-Saharan Africa. Transient increases in HIV viral load (VL), or blips, have been described following routine vaccinations. We characterized VL blips among PLWH enrolled in a phase 2 trial of a heterologous two-dose EVD vaccine. Methods In EBL2003, adult participants with and without HIV were randomized 1:4 to receive placebo or vaccine. Part A in the US studied MVA-BN-Filo followed by Ad26.ZEBOV 14 days later. Part B in Africa evaluated this MVA/Ad26 regimen and also a schedule of Ad26.ZEBOV followed by MVA-BN-Filo 29 days later. VL was assessed at screening, pre-vaccination, and 21, 42, 180, and 365 days post dose 2. Participants with VL < 20 copies/mL at the first 2 visits who received both doses and had complete VL data through 42 days post dose 2 were evaluated. Blips were defined as a post-injection VL ≥ 20 copies/mL no later than 42 days post dose 2, with subsequent return to VL < 20 copies/mL. Results A total of 277 PLWH on antiretroviral therapy (ART) were assessed; 73.3% (203) had baseline virologic suppression, and 89.2% (181) of those received both doses with complete VL data for inclusion in the analysis. Overall, 19.9% (36) experienced blips: 20.0% (29) of vaccinees vs 19.4% (7) of placebo recipients (p=1.0). All baseline suppressed participants with post-injection viremia subsequently regained suppression. Among vaccinees, the mean blip VL was 192 copies/mL, and the mean blip duration was 56 days, which was not significantly different from placebo. Of all blips, only 2 were > 1,000 copies/mL. Blips occurred in 24.0% (25) of Ad26/MVA recipients, and 9.7% (4) of MVA/Ad26 recipients (p=0.07). A dose of Ad26 was associated with a blip in 6.9% (10) of recipients vs 13.1% (19) for MVA recipients (p=0.12). Regardless of regimen, dose 1 was associated with a blip in 8.3% (12) of vaccinees, compared to 11.7% (17) of vaccinees for dose 2 (p=0.43). Conclusion Among successfully treated PLWH, we observed low magnitude post-dose HIV blips that were not more common in vaccine vs. placebo recipients and did not result in loss of virologic suppression. This data is favorable for the deployment of the EVD vaccines in this trial in areas of high HIV endemicity. Disclosures Benjamin L. Custer, M.D., Alexion Pharmaceuticals (Shareholder)Armata Pharmaceuticals (Shareholder)Biomarin Pharmaceutical (Shareholder)Crispr Therapeutics (Shareholder)CVS Health Corp (Shareholder)Editas Medicine (Shareholder)Gilead (Shareholder)Glaxo Smith Kline (Shareholder)Hologic Inc (Shareholder)Merck (Shareholder)Mesoblast LTD (Shareholder)Pfizer (Shareholder)Sanofi (Shareholder)Unitedhealth Group (Shareholder)Vertex Pharmaceuticals (Shareholder) Georgi Shukarev, MD, Janssen (Employee) Auguste Gaddah, PhD, Janssen Pharmaceutica N.V (Employee) Kerstin Luhn, PhD, Janssen Vaccines and Prevention (Employee, Shareholder) Macaya Douoguih, MD, MPH, Janssen (Employee) Cynthia Robinson, MD, Janssen Vaccines (Employee)

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico

BACKGROUND Vaccination using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein antigen has been effective in the prevention of coronavirus disease 2019 (Covid-19). NVX-CoV2373 is an adjuvanted, recombinant S protein nanoparticle vaccine that demonstrated clinical efficacy for prevention of Covid-19 in phase 2b/3 trials in the United Kingdom and South Africa. METHODS This phase 3, randomized, observer-blinded, placebo-controlled trial evaluated the efficacy and safety of NVX-CoV2373 in adults ≥18 years of age in the United States and Mexico during the first quarter of 2021. Participants were randomized in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary end point was vaccine efficacy (VE) against reverse transcriptase-polymerase chain reaction-confirmed Covid-19 in SARS-CoV-2-naive participants ≥7 days after the second dose administration. RESULTS Of the 29,949 participants randomized between December 27, 2020, and February 18, 2021, 29,582 (median age: 47 years, 12.6% ≥65 years) received ≥1 dose: 19,714 received vaccine and 9868 placebo. In the per-protocol population, there were 77 Covid-19 cases; 14 among vaccine and 63 among placebo recipients (VE: 90.4%, 95% confidence interval [CI] 82.9 to 94.6, P<0.001). All moderate-to-severe cases occurred in placebo recipients, yielding VE of 100% (95% CI 87.0 to 100). Most sequenced viral genomes (48/61, 78.7%) were variants of concern (VOC) or interest (VOI), mainly represented by variant alpha/B.1.1.7 (31/35, 88.6% VOC identified). VE against any VOC/VOI was 92.6% (95% CI 83.6 to 96.7). Reactogenicity was mostly mild-to-moderate and transient, but more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments. CONCLUSIONS NVX-CoV2373 was well tolerated and demonstrated a high overall VE (>90%) for prevention of Covid-19, with most cases due to variant strains. (Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802.)

Efficacy, safety, and lot to lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): a double-blind, randomised, controlled phase 3 trial

Background: We report the clinical efficacy against COVID 19 infection of BBV152, a whole virion inactivated SARS CoV 2 vaccine formulated with a Toll like receptor 7/8 agonist molecule adsorbed to alum (Algel IMDG). Methods: We did a double-blind, randomised, multicentre, phase 3 clinical trial in 25 Indian hospitals to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Healthy adults (age 18 to 98 years) randomised 1:1 using a sponsor-supplied randomisation scheme received two intramuscular doses of vaccine or placebo administered four weeks apart. The primary outcome was laboratory confirmed symptomatic COVID 19, occurring at least 14 days after the second dose. Secondary outcomes were efficacy in subgroups for age (18 to < 60 years and >=60 years) and in participants with pre-existing stable medical conditions. We also evaluated safety, reactogenicity, and consistency of immune responses for three consecutive manufacturing lots. Findings: Between November 16, 2020 and January 7, 2021 we recruited 25,798 participants who were randomised to BBV152 or placebo groups; 24,419 received two doses of BBV152 (n = 12,221) or placebo (n = 12,198). In a case-driven analysis, 130 cases of symptomatic COVID-19 were reported in 16,973 (0.77%) participants with follow-up at least two weeks after the second vaccination; 24 occurred in the vaccine group and 106 in placebo recipients giving an overall vaccine efficacy of 77.8% (95% CI: 65.2,86.4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93.4% (57.1,99.8). Efficacy against asymptomatic COVID 19 was 63.6% (29.0, 82.4). BBV152 conferred 65.2% (95% CI: 33.1, 83.0) protection against the SARS CoV 2 Variant of Concern, B.1.617.2 (Delta). BBV152 was well tolerated with no clinically or statistically significant differences in the distributions of solicited, unsolicited, or serious adverse events between vaccine and placebo groups. No cases of anaphylaxis or vaccine-related deaths were reported. Interpretation: BBV152 was immunogenic and highly efficacious against symptomatic and asymptomatic COVID 19 variant associated disease, particularly against severe disease in adults. Vaccination was well tolerated with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other COVID-19 vaccines.

Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant

ABSTRACTBackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use.MethodsIn this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 µg recombinant spike protein with 50 µg Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy ≥7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants.ResultsA total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups.ConclusionsThe NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)

Evaluating the Long-Term Efficacy of COVID-19 Vaccines

Large-scale deployment of safe and durably effective vaccines can halt the COVID-19 pandemic.1–3 However, the high vaccine efficacy reported by ongoing phase 3 placebo-controlled clinical trials is based on a median follow-up time of only about two months4–5 and thus does not pertain to long-term efficacy. To evaluate the duration of protection while allowing trial participants timely access to efficacious vaccine, investigators can sequentially cross placebo recipients to the vaccine arm according to priority groups. Here, we show how to estimate potentially time-varying placebo-controlled vaccine efficacy in this type of staggered vaccination of placebo recipients. In addition, we compare the performance of blinded and unblinded crossover designs in estimating long-term vaccine efficacy.SummaryWe show how to estimate potentially waning long-term efficacy of COVID-19 vaccines in randomized, placebo-controlled clinical trials with staggered enrollment of participants and sequential crossover of placebo recipients.

Baloxavir Treatment in Adolescents With Acute Influenza: Subgroup Analysis From the CAPSTONE-1 Trial

Background Baloxavir marboxil has demonstrated safety and efficacy in treating adult and adolescent outpatients with acute influenza (CAPSTONE-1 trial). Here, we report a subgroup analysis of outcomes in adolescents from the trial. Methods CAPSTONE-1 was a randomized, double-blind, placebo-controlled study. Eligible adolescent outpatients (aged 12-17 years of age) were randomized in a ratio of 2:1 to a single dose of baloxavir 40/80 mg if less than/greater than or equal to 80 kg or placebo. The main outcomes were the time to alleviation of symptoms (TTAS), duration of infectious virus detection, and incidence of adverse events (AEs). Results Among 117 adolescent patients, 90 (77%) comprised the intent-to-treat infected population (63 baloxavir and 27 placebo; 88.9% A(H3N2)). The median TTAS was 38.6 hours shorter (95% confidence interval: −2.6, 68.4) in the baloxavir group compared with placebo (median TTAS, 54.1 hours vs 92.7 hours, P = .0055). The median time to sustained cessation of infectious virus detection was 72.0 hours for baloxavir compared with 120.0 hours for placebo recipients (P &lt; .0001). Treatment-emergent PA/I38X-substituted viruses were detected in 5 of the 51 (9.8%) baloxavir recipients. In the safety population (76 baloxavir and 41 placebo), AEs were less common in baloxavir than placebo recipients (17.1% vs 34.1%; P = .0421). In the baloxavir group, no AEs except for diarrhea were reported in 2 or more patients. Conclusions Baloxavir demonstrated clinical and virologic efficacy in the otherwise healthy adolescents with acute influenza compared with placebo. There were no safety concerns identified. These results were similar to the adult population in CAPSTONE-1 and support baloxavir as a treatment option in adolescents.

RV144 HIV-1 vaccination impacts post-infection antibody responses

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection.

632. A Randomized, Placebo-Controlled, Double-Blind, Clinical Trial Evaluating Two Dose Regimens of Rifaximin (550mg daily or twice-daily) for Chemoprophylaxis Against Travelers’ Diarrhea Among Deployed U.S. and U.K. Military Personnel (PREVENT TD)

Background Travelers’ diarrhea (TD) is a leading threat to military readiness. Most trials of rifaximin chemoprophylaxis involve civilians or short-duration travel, whereas military travelers are exposed for longer periods at austere locations and are often physically taxed. We sought to assess efficacy of two regimens among military personnel deployed overseas. Methods This was a multi-site, double-blind, placebo-controlled trial of deployed military, randomized to placebo, rifaximin 550 mg daily, or rifaximin 550 mg twice-daily, for up to 42 days (1:1:1; 6 randomizations/block). Diaries were reviewed with subjects on return. Primary endpoint was time to first unformed stool (TFUS) in a TD episode. Other endpoints were assessed by intention to treat (ITT) and subgroups included incidence of any loose stool, meeting criteria for TD, safety, efficacy, adherence and impact to activity endpoints. Results 343 subjects were included in the ITT population. All UK travelers deployed to a single-site in Kenya; US travelers mostly deployed to various Asia-Pacific locations. Of 73 (21.2%) subjects reporting diarrhea, 42 (57.5%) met TD criteria. Among rifaximin-treated subjects, 15.9% (n=17) reported diarrhea in the twice-daily arm, 20.7% (n=25) in the daily arm, vs. 27.0% (n=31) of placebo recipients; p=.04 and 0.26 respectively. TD was reported by 10.3% (n=11) and 10.7% (n=13) in the daily and twice-daily arms, vs. 15.7% (n=18) among placebo recipients; p=0.24 vs. 0.26 respectively. Among UK personnel, a twice-daily regimen vs. placebo resulted in significantly fewer TD episodes (1.6% vs. 11.9%; p=0.03). Adverse events were similar between groups. Table 1: Demographics, endpoints, and adverse events (Comparisons are across placebo vs. each dosing regimen. Intent-to-treat [ITT] population defined as subjects enrolled into the study, randomized, travelled and had follow-up. p-values calculated from chi-square or Fisher’s exact test [categorical variables] and Wilcoxon-Mann-Whitney test [continuous variables]. Analyses performed on SAS v9.4. BID: twice-daily) Conclusion This is the first trial comparing two high-dose regimens of rifaximin prophylaxis in deployed personnel. Unlike prior reports, neither regimen was associated with an overall significant decrease in TD, potentially due to low overall TD incidence. However, the twice-daily regimen was associated with a numerically lower incidence of diarrheal stool, and in the UK subject group, there was a significant decrease of both TD and diarrheal stool. The impact of variability in regional TD risk, pathogen distribution and adherence in austere deployment environments on efficacy will be reviewed. Disclosures All Authors: No reported disclosures