Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam

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作者: Hsieh, Ching-Lin ; Scharf, Rami ; Dinh Vu, Thiem ; Thi Van Pham, Anh ; Mercer, Laina D ; Mai Nguyen, Huong ; Chinwangso, Pailinrut ; Slamanig, Stefan ; Van Le, Be ; Sun, Weina ; Martinez, Jose L ; Lawpoolsri, Saranath ; White, Jessica A ; Palese, Peter ; Lal, Manjari ; Hai Vu, Ha ; Innis, Bruce L ; Manuel Carreño, Juan ; Gonzalez-Dominguez, Irene ; Van Nguyen, Duoc ; McLellan, Jason S ; Thanh Ta, Van ; Krammer, Florian ; Garcia-Sastre, Adolfo ; Duc Dang, Anh ; Minh Vu, Huong ; Thi Ngoc Dang, Mai ; Raskin, Ariel ; Raghunandan, Rama ; Huu Duong, Thai ; Tcheou, Johnstone ; Cong Tran, Thang ; Hjorth, Richard

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state. Vaccine production and clinical development was initiated in Vietnam, Thailand, and Brazil. Here the interim results from the first stage of the randomized, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial conducted at the Hanoi Medical University (Vietnam) are presented. Healthy adults aged 18-59 years, non-pregnant, and with self-reported negative history for SARS-CoV-2 infection were eligible. Participants were randomized to receive one of five treatments by intramuscular injection twice, 28 days apart: 1 μg +/- CpG1018 (a toll-like receptor 9 agonist), 3 μg alone, 10 μg alone, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited adverse events (AEs) during 7 days and subject-reported AEs during 28 days after each vaccination. Investigators further reviewed subject-reported AEs. Secondary outcomes were immunogenicity measures (anti-spike immunoglobulin G [IgG] and pseudotyped virus neutralization). This interim analysis assessed safety 56 days after first vaccination (day 57) in treatment-exposed individuals and immunogenicity through 14 days after second vaccination (day 43) per protocol. Between March 15 and April 23, 2021, 224 individuals were screened and 120 were enrolled (25 per group for active vaccination and 20 for placebo). All subjects received two doses. The most common solicited AEs among those receiving active vaccine or placebo were all predominantly mild and included injection site pain or tenderness (<58%), fatigue or malaise (<22%), headache (<21%), and myalgia (<14%). No higher proportion of the solicited AEs were observed for any group of active vaccine. The proportion reporting vaccine-related AEs during the 28 days after either vaccination ranged from 4% to 8% among vaccine groups and was 5% in controls. No vaccine-related serious adverse event occurred. The immune response in the 10 μg formulation group was highest, followed by 1 μg + CpG1018, 3 μg, and 1 μg formulations. Fourteen days after the second vaccination, the geometric mean concentrations (GMC) of 50% neutralizing antibody against the homologous Wuhan-Hu-1 pseudovirus ranged from 56.07 IU/mL (1 μg, 95% CI 37.01, 84.94) to 246.19 IU/mL (10 μg, 95% CI 151.97, 398.82), with 84% to 96% of vaccine groups attaining a ≥ 4-fold increase over baseline. This was compared to a panel of human convalescent sera (N = 29, 72.93 95% CI 33.00-161.14). Live virus neutralization to the B.1.617.2 (Delta) variant of concern was reduced but in line with observations for vaccines currently in use. Since the adjuvant has shown modest benefit, GMC ratio of 2.56 (95% CI, 1.4-4.6) for 1 μg +/- CpG1018, a decision was made not to continue studying it with this vaccine. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 μg dose was advanced to phase 2 along with a 6 μg dose. The 10 μg dose was not selected for evaluation in phase 2 due to potential impact on manufacturing capacity. ClinicalTrials.gov NCT04830800.

A Newcastle disease virus-vector expressing a prefusion-stabilized spike protein of SARS-CoV-2 induces protective immune responses against prototype virus and variants of concern in mice and hamsters

作者: Garcia-Sastre, Adolfo ; Krammer, Florian ; Amanat, Fatima ; Oliveira, Ricardo ; Rosado, Victoria ; Innis, Bruce ; Jangra, Sonia ; Schotsaert, Michael ; Sano, Kaori ; Slamanig, Stefan ; Mena, Ignacio ; Rathnasinghe, Raveen ; González-Domínguez, Irene ; Thai, Duong Huu ; Sun, Weina ; Palese, Peter ; Lemus, Nicholas ; McCroskery, Stephen ; Wirachwong, Ponthip ; Martinez, Jose ; Coughlan, Lynda ; Liu, Yonghong ; Raghunandan, Rama ; Scharf, Rami ; Hjorth, Richard

AbstractRapid development of coronavirus disease 2019 (COVID-19) vaccines and expedited authorization for use and approval has been proven beneficial to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread and given hope in this desperate situation. It is believed that sufficient supplies and equitable allocations of vaccines are necessary to limit the global impact of the COVID-19 pandemic and the emergence of additional variants of concern. We have developed a COVID-19 vaccine based on Newcastle disease virus (NDV) that can be manufactured at high yields in embryonated eggs. Here we provide evidence that the NDV vector expressing an optimized spike antigen (NDV-HXP-S), upgraded from our previous construct, is a versatile vaccine that can be used live or inactivated to induce strong antibody responses and to also cross-neutralize variants of concern. The immunity conferred by NDV-HXP-S effectively counteracts SARS-CoV-2 infection in mice and hamsters. It is noteworthy that vaccine lots produced by existing egg-based influenza virus vaccine manufacturers in Vietnam, Thailand and Brazil exhibited excellent immunogenicity and efficacy in hamsters, demonstrating that NDV-HXP-S vaccines can be quickly produced at large-scale to meet global demands.

Nature Communications1区 · 综合性期刊

A Newcastle disease virus expressing a stabilized spike protein of SARS-CoV-2 induces protective immune responses

1区 · 综合性期刊

ArticleOA

作者: Jangra, Sonia ; Rosado, Victoria ; Raghunandan, Rama ; Krammer, Florian ; Amanat, Fatima ; Innis, Bruce L ; Sano, Kaori ; Slamanig, Stefan ; Scharf, Rami ; Oliveira, Ricardo Das Neves ; Hjorth, Richard ; Martinez, Jose L ; González-Domínguez, Irene ; Palese, Peter ; McCroskery, Stephen ; Sun, Weina ; Schotsaert, Michael ; Coughlan, Lynda ; Thai, Duong Huu ; Lemus, Nicholas ; García-Sastre, Adolfo ; Rathnasinghe, Raveen ; Mena, Ignacio ; Liu, Yonghong ; Wirachwong, Ponthip

AbstractRapid development of COVID-19 vaccines has helped mitigating SARS-CoV-2 spread, but more equitable allocation of vaccines is necessary to limit the global impact of the COVID-19 pandemic and the emergence of additional variants of concern. We have developed a COVID-19 vaccine candidate based on Newcastle disease virus (NDV) that can be manufactured at high yields in embryonated eggs. Here, we show that the NDV vector expressing an optimized spike antigen (NDV-HXP-S) is a versatile vaccine inducing protective antibody responses. NDV-HXP-S can be administered intramuscularly as inactivated vaccine or intranasally as live vaccine. We show that NDV-HXP-S GMP-produced in Vietnam, Thailand and Brazil is effective in the hamster model. Furthermore, we show that intramuscular vaccination with NDV-HXP-S reduces replication of tested variants of concerns in mice. The immunity conferred by NDV-HXP-S effectively counteracts SARS-CoV-2 infection in mice and hamsters.

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