The development and distribution of effective vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for the coronavirus disease 2019 (COVID-19), is estimated to have already saved the lives of hundreds of thousands of people in the United States alone.
In addition to the vaccines that have already been approved for use in many countries around the world, new SARS-CoV-2 vaccines with improved performance characteristics are still being developed. A new study reports the safety and immunogenicity of Nanocovax, which is a recombinant full-length prefusion stabilized recombinant SARS-CoV-2 spike (S-2P) adjuvanted with aluminum hydroxide.
Study: Safety and Immunogenicity of Nanocovax, a SARS-CoV-2 Recombinant Spike Protein Vaccine. Image Credit: Tawat / Shutterstock.com
SARS-CoV-2 is a betacoronavirus with multiple spike proteins protruding from the viral envelope. The spike antigen mediates attachment to the host cell angiotensin-converting enzyme 2 (ACE2) receptor and, subsequently, the viral entry into the cell to trigger viral transcription and replication of new virions. The spike protein is a heavily glycosylated protein, with glycans having an important role in its antigenicity.
Nanocovax is a protein subunit vaccine that has been developed by Nanogen Pharmaceutical Biotechnology JSC., which contains the full-length spike stabilized by the addition of two prolines (S2P). The Nanocovax has already been tested in animal models and demonstrated its ability to induce high anti-spike antibody levels.
Microneutralization assays showed high neutralizing antibody titers against the Wuhan variant. Surrogate virus neutralization tests were also carried out to validate these findings.
Phase 1 trial results
In Phase 1 trials conducted at the Military Medical University in Ha Noi, Vietnam in December 2020, the safety and immunogenicity of the Nanocovax doses of 25 micrograms (µg), 50 µg, and 75 µg in healthy adults.
The study included 60 participants, with equal numbers receiving each dose in a phased manner. The lowest doses were administered first, with escalation after 72 hours provided no severe adverse events (SAEs) were observed. Two doses of this vaccine were given 28 days apart. No SAEs were observed, reactions were absent or mild, and the vaccine appeared to be safe at all three dosage levels.
Phase 2 trial results
Phase 2 trials were carried out at Military Medical Academy in Ha Noi and the Pasteur Institute in Ho Chi Minh, Vietnam. A total of 560 participants were given the same doses at the same intervals, with 160 volunteers receiving each dose of the vaccine and 80 receiving the placebo.
Local adverse effects including pain were reported in 32.6% and 32.1% of the subjects after the first and the second doses, respectively. Systemic effects including fatigue and headache were found in about 16.9% and 13.3% of participants after each injection, respectively. Fever was rare but was reported in 3.8% of participants after both doses.
SAEs were rare; however, severe back pain was reported in three patients, whereas one patient exhibited serious sepsis, and another patient experienced a severe sore throat. Milder adverse effects such as cough and sore throat were seen in less than 5% of subjects.
Overall, adverse events were observed within two days and often resolved in seven days. No obvious relationship was observed between dose escalation and adverse events. The rate of adverse events was about 27% and 34% in the vaccinated and placebo groups, respectively.
Laboratory aberrations such as hyperglycemia and leukocytosis were also reported. However, neither phase paused vaccinations because of adverse events. Some of the events, such as angina following a stent graft, sepsis, abscesses, personal injury, and anaphylaxis, were not related to the vaccination, the scientists found.
The immunoglobulin G (IgG) titer of anti-spike antibodies rose steeply after the second injection at all dosages. At five weeks after the second dose, at approximately 7, 9, and 13 Units (U)/mL respectively, as compared to undetectable titers prior to the first dose.
At six weeks, the titers rose to 60, 49, and 57 U/mL respectively, compared to 0.3 U/mL in the placebo group at both time points.
The fold increase in geometric mean concentration (GMC), which is also known as the geometric mean fold rise (GMFR), of the anti-spike IgG antibodies, was 36-, 35-, and 50-fold at day 35, but 230-, 180-, and 220-fold at day 42, as compared to 1 with the placebo group. Seroconversion, or GMFR of 4 or more, was observed in approximately 85% on day 35, but almost 100% on day 42.
Surrogate virus neutralization test (sVNT) results reflect the percentage of inhibition but must be over 30% to be positive. On day 35, the average sVNT in the vaccinated groups was 60-70%, with over 80-85% of subjects being positive. On day 42, the mean sVNT increased to 87% and all patients were positive.
What are the implications?
“The results of these Phase 1 and Phase 2 studies demonstrated an excellent safety profile of Nanocovax, regardless of dose strengths. Most adverse events and serious adverse events were grade 1 which disappeared within 48 hours after injection.”
Not only is reactogenicity reduced, but neutralizing ability appears to be higher, irrespective of the dose. Neutralizing anti-spike IgG antibodies were generated by the vaccine.
No immune cellular responses were found, which may be due to the addition of the aluminum adjuvant. Phase 3 trials will examine T-cell responses in a smaller study, with T-cells being exposed to T-helper cells type 2 (Th2) cytokines. The risk of vaccine-associated enhanced respiratory disease (ERD) is a real concern and requires further investigation.
‘In conclusion, Nanocovax is highly safe and immunogenic. Dose strength of 25 mcg is selected for phase 3 to evaluate the vaccine efficacy.”
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.