Prefusion SARS-CoV-2 spike-based vaccine candidate shows high safety and efficacy in phase I trial

Many vaccines are being trialed against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the enveloped virus causing the current coronavirus disease 2019 (COVID-19) pandemic.

Newer and more effective vaccines are urgently required due to the rapid emergence of highly transmissible and perhaps more virulent virus lineages that often confer immune escape. Along with this observation, it is pertinent that global immunization will take months, if not years, to complete.

During this time, hundreds of thousands of severe COVID-19 cases will need to be treated, making new vaccines a priority to prevent the overwhelming of health services.

A new preprint research paper posted to the medRxiv* server reports the results of the first human trial of the prefusion stabilized SARS-CoV-2 spike vaccine MVC-COV1901 in Taiwan.

Study: First-in-Human Trial of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine with Adjuvant of Aluminum Hydroxide and CpG 1018. Image Credit: Design_Cells / Shutterstock

Stabilized vaccine design

A vaccine must use an immunogenic antigen in the right conformation to elicit a protective neutralizing response.

In the current case, SARS-CoV-2 mediates attachment to the host cell via a receptor called the angiotensin-converting enzyme 2 (ACE2) by its spike protein.

Neutralizing antibodies to this virus often block ACE2-spike binding to prevent infection from occurring. The spike has a prefusion and postfusion state. To stabilize it in the prefusion state, a pair of proline residues is added to obtain S-2P – the stabilized prefusion S ectodomain of the spike protein.

This recombinant protein also has a GSAS substitution which eliminates the furin cleavage site at the S1/S2 interface and a trimerization motif at the C4 end.

Cryo-electron microscopy shows that it is in the prefusion state and capable of ACE2 binding.

The MVC-COV1901 vaccine was formulated with the help of an adjuvant, CpG 1018, and aluminum hydroxide. The former behaves as a Toll-like receptor 9, to increase the immune response following exposure while inducing a Th1-skewed immune response.

Study details

The phase I study of MVC-COV1901 included 45 healthy adults between 20 and 49 years, who received two doses each, but in high, medium, and low dosages. The interval between two doses was 28 days.

The study found that all three dosage groups had the same frequency of mild adverse events. Fever was not reported by any subject. One patient had tiredness and a feeling of being unwell.

The spike-specific immunoglobulin G (IgG) antibody titer was markedly increased after the boost dose, with peak geometric mean titers (GMT) at 7,000 for the low-dosage group, 7,7000 for the medium dosage, and 11,000 for the high-dose groups, respectively.

The mean GMTs were similar to those of a set of convalescent serum samples. Seroconversion occurred in all high and medium dosage vaccine recipients by day 57. Serum from participants in these groups showed neutralizing activity except for the low-dosage group.

Here too, the GMTs were similar to convalescent serum samples, at 52,000 and 82,000 in the medium- and high-dose groups, respectively.

What are the implications?

The study thus shows that the MVC-COV1901 vaccine, a stabilized prefusion spike-based adjuvanted vaccine, is safe, well-tolerated, and immunogenic in healthy adults up to 49 years. With the baseline neutralizing response being zero in all groups, this bears out the fact that the SARS-CoV-2 is currently not being transmitted in Taiwan, where the study was performed.

Complete seroconversion was noted in all recipients of medium and high vaccine doses. The IgG titers correlated well with neutralizing activity against the wild-type virus.

Further research will be needed to understand how this translates into protection against infection. However, earlier research on other viruses indicates that serum neutralizing activity is a biomarker of the protective antibody response.

Preclinical studies in hamsters showed the ability of this vaccine candidate to protect against SARS-CoV-2 after two doses. Moreover, the GMTs are similar to the mean GMT of a panel of convalescent sera.

Further follow-up for humoral immunity will continue until six months are over. The trial is now in phase 2, including 3,700 participants, some of whom are older adults and/or have pre-existing diseases, both of which increase the risk for COVID-19.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.