China's COVID-19 Vaccine BBIBP-CorV Based On Inactivated Whole SARS-CoV-2 Virus Shows To Be A Safe Promising Candidate For Short Term Protection

Vaccine-COVID-19: As more studies are showing that antibodies will ultimately only provide short term optimal protection of anything between 10 to 16 weeks and while at the same time other studies are also showing that many AAV (Adeno Associated Virus) vector RNA vaccines that are currently being developed and are in phase 3 trials might actually cause certain adverse effects https://www.thailandmedical.news/news/breaking-covid-19-vaccine-exclusive-possible-dangers-of-using-adeno-associated-virus-aav-vectors-for-covid-19-vaccines-), the good old fashioned tried platforms of live attenuated vaccines (LAV)  and inactivated vaccines with whole virus (IAWVV) are proving to be more reliable after all in terms of providing a short-term protection to individuals.


 
While India is working on some interesting LAV COVID-19 vaccine candidates, the Chinese have developed a vaccine candidate based on the inactivated whole SARS-CoV-2 virus (BBIBP-CorV) which has proven to be safe and elicits an antibody response according to the findings from a small early-phase randomized clinical trial.
 
In this phase 1/2 trial, the BBIBP-CorV inactivated vaccine, given as a two-dose immunisation, was safe and well tolerated at all three doses in both age groups. A robust humoral immune response was observed in 100% of vaccine recipients. In preclinical studies, the study team showed that immunisation with BBIBP-CorV can induce high levels of neutralising antibody titres in mice, rats, guinea pigs, rabbits, and non-human primates (cynomolgus monkeys and rhesus macaques) to provide protection against SARS-CoV-2. https://pubmed.ncbi.nlm.nih.gov/32778225/
 
The study results of this trial were published in the peer reviewed journal: Lancet Infectious Diseases. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30831-8/fulltext
 
Interestingly a previous clinical trial reported similar results for a different vaccine that is also based on inactivated whole SARS-CoV-2 virus, but in that study the vaccine was only tested in people aged under 60 years. https://jamanetwork.com/journals/jama/article-abstract/2769612
 
The current clinical trial included participants aged between 18 and 80 years, and found that antibody responses were induced in all recipients. Participants aged 60 and over were slower to respond, taking 42 days before antibodies were detected in all recipients compared with 28 days for participants aged 18-59. Antibody levels were also lower in those aged 60-80 years compared with those aged 18-59 (Mean neutralising antibody titre 42 days after receiving a 8μg vaccine dose was 228.7 for people aged 18-59, and 170.9 for those aged 60-80).
 
The clinical trial was not designed to assess efficacy of the vaccine, so it is not possible to say whether the antibody responses induced by the vaccine, called BBIBP-CorV, are sufficient to protect from S ARS-CoV-2 infection.
 
Dr Xiaoming Yang, one of the authors of the study, a professor from the Beijing Institute of Biological Products Company Limited, Beijing, China, told Thailand Medical news, "Protecting older people is a key aim of a successful COVID-19 vaccine as this age group is at greater risk of severe illness from the disease. However, vaccines are sometimes less effective in this group because the immune system weakens with age. It is therefore encouraging to see that BBIBP-CorV induces antibody responses in people aged 60 and older, and we believe this justifies further investigation."
 
To date there are 42 COVID-19 vaccines in clinical trials.
 
These vaccines vary in type and include DNA plasmid vaccines, inactivated virus vaccines, adenovirus-vectored vaccines, RNA vaccines, protein subunit vaccines and virus-like particle vaccines.
 
There have been claims that some of these have already been shown to be safe and to elicit immune responses in early phase clinical trials.
 
Significantly the BBIBP-CorV vaccine used in the study reported here is based on a sample of the virus that was isolated from a patient in China. The genomic sequencing of the virus has been identified and the strain code is 19nCoV-CDC-Tan-HB02 .
 
Subsequent stocks of the virus were grown in the lab using cell lines and then inactivated using a chemical called beta-proprionolactone. BBIBP-CorV includes the killed virus mixed with another component, aluminium hydroxide, which is called an adjuvant because it is known to boost immune responses.
 
The clinical first phase trial of the study was designed to find the optimal safe dose for BBIBP-CorV. It involved 96 healthy volunteers aged between 18 and 59 years and a second group of 96 participants aged between 60 years and 80 years. Within each group, the vaccine was tested at three different dose levels (2μg, 4μg and 8μg, 24 participants per group), with two vaccinations administered on day 0 and 28. A fourth group within each age group (24 participants in each age group) were given two doses of a placebo vaccine. In total, in phase 1 of the study, 144 participants received the vaccine and 48 received the placebo.
 
The clinical phase 2 trial of the study was designed to identify the optimal timing schedule for vaccination. 448 participants aged between 18 and 59 years were randomly assigned to receive either one 8?g shot of vaccine or placebo, or two shots of 4μg vaccine or placebo (at 0 and 14 days, 0 and 21 days or 0 and 28 days). In this second phase, there were 112 participants per group, with 336 receiving the vaccine, and 112 receiving the placebo.
 
Clinical trial participants were asked to report any adverse events for the first seven days after each vaccination and these were verified by the research team. Thereafter, participants recorded any adverse events using paper cards for the following 4 weeks. During phase 1, laboratory tests were carried out after the first and second vaccinations to assess kidney function, liver function and other organ functions. Blood samples were taken to test antibody levels for SARS-CoV-2 before and after vaccination.
 
Importantly no serious adverse events were reported within 28 days of the final vaccination. The most common side effect was pain at the injection site (phase 1 results: 24% [34/144] of vaccine recipients, vs 6% [3/48] of placebo recipients). A small number of participants reported experiencing a fever (phase 1 results: 4% [5/144] of vaccine recipients, vs 6% [3/48] of placebo recipients). There were no instances of clinically significant changes in organ functions detected in laboratory tests in any of the groups.
 
Significantly the greatest antibody responses were elicited by two 4μg doses of the vaccine at either days 0 and 21 or 0 and 28 (Mean neutralising antibody titres 28 days after second vaccination were 282.7 for two 4μg injections at day 0 and 21, and 218.0 for two 4μg injections at day 0 and 28).
 
Dr Yang added, "Our trial findings indicate that a booster shot is necessary to achieve the greatest antibody responses against SARS-CoV-2 and could be important for protection. This provides useful information for a phase 3 trial."
 
The researchers noted some limitations with the study, including the short duration of follow up at just 42 days. They also highlighted that the study did not include children and adolescents aged under 18. Trials with these groups will be carried out when the full analysis of data from adult groups is completed, the researchers say.
 
Commenting in a linked article, Professor Dr Larisa Rudenko, who was not involved in the study, from the Institute of Experimental Medicine, Saint Petersburg, Russia, said, ”more studies are needed to establish whether the inactivated SARS-CoV-2 vaccines are capable of inducing and maintaining virus-specific T-cell responses, because CD4-positive T-cell help is important for optimal antibody responses, as well as for cytotoxic CD8-positive T-cell activation, which, in turn, are crucial for viral clearance if neutralizing antibody-mediated protection is incomplete."
 
Evidence to indicate antibody-dependent enhancement in SARS-CoV infection has emerged in certain studies. https://pubmed.ncbi.nlm.nih.gov/15642942/
and https://pubmed.ncbi.nlm.nih.gov/27627203/
 
However, in preclinical studies of BBIBP-CorV immunisation and SARS-CoV-2 challenge, no antibody-dependent enhancement was observed in rhesus macaques. https://pubmed.ncbi.nlm.nih.gov/32778225/
 
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