Safety and immunogenicity of a live recombinant Newcastle disease virus-based COVID-19 vaccine (Patria) administered via the intramuscular or intranasal route: Interim results of a non-randomized open label phase I trial in Mexico

Abstract

There is still a need for safe, efficient and low-cost coronavirus disease 2019 (COVID-19) vaccines that can stop transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we evaluated a vaccine candidate based on a live recombinant Newcastle disease virus (NDV) that expresses a stable version of the spike protein in infected cells as well as on the surface of the viral particle (AVX/COVID-12-HEXAPRO, also known as NDV-HXP-S). This vaccine candidate can be grown in embryonated eggs at low cost similar to influenza virus vaccines and it can also be administered intranasally, potentially to induce mucosal immunity. We evaluated this vaccine candidate in prime-boost regimens via intramuscular, intranasal, or intranasal followed by intramuscular routes in an open label non-randomized non-placebo-controlled phase I clinical trial in Mexico in 91 volunteers. The primary objective of the trial was to assess vaccine safety and the secondary objective was to determine the immunogenicity of the different vaccine regimens. In the interim analysis reported here, the vaccine was found to be safe and the higher doses tested were found to be immunogenic when given intramuscularly or intranasally followed by intramuscular administration, providing the basis for further clinical development of the vaccine candidate. The study is registered under ClinicalTrials.gov identifier NCT04871737 . Funding was provided by Avimex and CONACYT.

Conflict of interest statement

Conflict of interest statement

S.P.-R, J.J.C-M, P. S-D, Y.L-V and A.M. contributed to this study pro-bono and declare no competing interests.

Figures

Figure 1.. Study design and groups distribution.

(A) Schematic representation of the study timeline, indicating routes of administration, vaccination time points, and sample collection for immunogenicity analyses. The three different vaccination regiments tested; intramuscular (IM) followed by intramuscular (IM), intranasal (IN) followed by intranasal (IN), and intranasal (IN) followed by intranasal (IN) administration are show on the left. Time points of sample collection (0, 14, 21, 28, 42, 90, 180 and 365 days after the first vaccine dose administration) and time points of vaccine administration (indicated by the red syringe) are shown on the right. (B) Diagram depicting specimen types collected to assess immunogenicity. (C) Subgroup characteristics and demographic information of participants of the trial (n=91).

Figure 2.. Enrollment and sub-randomization.

Diagram representing number of participants initially screened (n=142), failed enrollment criteria (n=48), early withdrawals (n=3), and eligible participants (n=90) that were included in the trial and assigned to any of the three vaccination regimens (n=30, per group) and dose (low n=10, medium n=10, high=10). A participant that initially was considered eligible and received an IM-IM regimen, but subsequently failed study criteria is indicated on the left.

Figure 3.. Local and systemic solicited adverse reactions.

Adverse events (AE) were registered according to the standardized MedDRA dictionary terms and classified as mild, moderate, or severe according to ICH/E6R2 Good Clinical Practices definitions. (A) Adverse reactions reported by the trial participants within 7 days after the first and second vaccine doses are shown. (B) Systemic reactions reported by the trial participants throughout the observational period are shown. In both A and B, mild, moderate, and severe adverse reactions are shown in the individuals receiving either of the three vaccination regimens and data is stratified by the vaccine dose received (LD=low dose, MD=medium dose, and HD=high dose).

Figure 4.. Spike-reactive antibody levels in sera from vaccinated volunteers.

Antibodies against the S1 subunit of the spike protein (which contains the receptor binding domain (RBD)) were measured in vaccinees’ sera by ELISA at baseline, and 14, 21, 28, and 42 days after the first vaccine dose administration. Individuals receiving the IM-IM regimen (left column), IN-IN regimen (middle column), or IN-IM (right column), with a high dose (top row), medium dose (middle row), or low dose (bottom row) of the vaccine are shown. Human convalescent serum (HCS) samples were added as additional controls. The limit of detection (LoD) is indicated by the horizontal dotted line. Negative values are indicated as half of the LoD. Statistical significance is indicated as follows: *P

Figure 5.. RBD-ACE2 interaction inhibiting antibodies in sera from vaccinated volunteers.

Antibodies binding to the receptor binding domain (RBD) that inhibited its interaction with the angiotensin-converting enzyme 2 (ACE2) were assessed in vaccinees’ sera using an RBD-ACE2 interaction inhibition assay at baseline and 14, 21, 28, and 42 days after the first vaccine dose administration. Individuals receiving the IM-IM regimen (left column), IN-IN regimen (middle column), or IN-IM (right column), with a high dose (top row), medium dose (middle row), or low dose (bottom row) of the vaccine are shown. Human convalescent serum (HCS) samples were added as additional controls. The cutoff established for positivity (30%) in this assay is indicated by the horizontal dotted line. Statistical significance is indicated as follows: *P

Figure 6.. Activation profile of spike-specific CD3+, CD4+ and CD8+ T cells after vaccination.

PBMCs were collected from vaccinees at baseline and 42 days after the first vaccine dose administration. Individuals receiving the IM-IM regimen (left column), IN-IN regimen (middle column), or IN-IM (right column) stratified by vaccine dose received (low, medium, or high) are shown. Activated CD3+ (top row), CD4+ (middle row), and CD8+ (bottom row) T cells were determined by flow cytometry after 18 h incubation with recombinant spike protein. Frequencies of T cells producing interferon gamma (IFN-γ) are presented. Statistical significance is indicated as follows: *P