Coronavirus (23) COVID-19 vaccine candidates in clinical trials: inactivated vaccines (c)

Continued from my last blog post.
3. Inactivated vaccine by the Institute of Medical Biology at the Chinese Academy of Medical Sciences (IMBCAMS)
The inactivated vaccine for COVID-19 developed by the Institute of Medical Biology at the Chinese Academy of Medical Sciences (IMBCAMS) started its phase 1-2 clinical trial in early July (NCT04470609), targeting 471 healthy volunteers aged above 60 in China.¹

According to the study design, it seems that the vaccine needs two injections, as with the other inactivated vaccines candidates. The enrolled subjects in phase 1 receive two doses of low-, medium-, or high-dose experimental vaccines, or placebo, at an interval of 28 days, while the enrolled subjects in phase 2 receive two doses of medium or high-dose experimental vaccines, or placebo, at an interval of 28 days. Information from ClinicalTrials.gov under the NIH of the USA indicates that the clinical trial is still ongoing and no study results have yet been published.

4. Covaxin^TM by Bharat Biotech International Ltd.
Covaxin^TM is the India's first indigenous COVID-19 vaccine.² It is co-developed by Bharat and the Indian Council of Medical Research (ICMR)-National Institute of Virology (NIV).

The vaccine received approval from India's regulatory agency for phase 1&2 human clinical trials, which have commenced across India since July.³ The study (NCT04471519) aims to recruit 1125 healthy volunteers, 375 in phase 1 and 750 in phase 2, to receive two intramuscular doses of the vaccine formulations 14 days apart. Information from ClinicalTrials.gov under the NIH of the USA indicates that the clinical trial is still ongoing and no study results have yet been published.³

Bharet Biotech sells vaccines of various platforms, including the inactivated vaccines, live-attenuated vaccines, and recombinant vaccines. The company has much experience in producing inactivated vaccines. Currently, they are selling 6 inactivated vaccine products which include vaccines for diphtheria, tetanus, pertussis, influenza A (H1N1), rabies, and Japanese Encephalitis. The development of an inactivated vaccine for COVID-19 is expected to show the company's ability to develop safe and high-efficacy vaccines.

Conclusion
Inactivated vaccine is one of the classic vaccine techniques. By using a denaturing agent, the infectious particles are denatured such that they can retain enough of their protein surfaces to set off a useful immune response. However, the tricky part of developing of an inactivated vaccine is the balance between inactivating the virus enough so that it cannot infect cells but not inactivate so much that it presents a totally different protein to the immune system and raises a response that cannot recognize the real virus.⁴ Therefore, the key to success relies on experience in development of inactivated vaccines which have been brought into the market. The biotech companies with products of inactivated vaccines on the market should have a higher chance of developing a COVID-19 vaccine with high efficacy and meeting safety standards.

Under normal conditions, the inactivated vaccine is more stable than RNA and other vaccine prototypes. According to the CEO of Sinovac, their inactivated vaccine against COVID-19, CoronaVac, has a shelf life of 3 years.⁵ The ease of preserving a vaccine cheaply means it can be more affordable in less-developed countries, and that distribution to a far-flung population is much less a problem.

However, it should be noted that inactivated vaccines do not generally provide protection as strong as live-attenuated vaccines, that is, weakened forms of pathogens. This is because inactivated vaccines are less like the natural infections than are the live-attenuated vaccines. Usually, at least 2 doses of the vaccine are required to provide sufficient protection. All 5 of the forefront inactivated vaccines mentioned in this blog required second injections.



References
1. https://web.archive.org/web/20200909094043/https://clinicaltrials.gov/ct2/show/record/NCT04470609
2. Bharat Biotech's website on Covaxin: https://www.bharatbiotech.com/covaxin.html
3. https://web.archive.org/web/20200909113422/https://clinicaltrials.gov/ct2/show/study/NCT04471519
4. SinoPharm's inactivated coronavirus vaccine. Derek Lowe. Science Translational Medicine. https://blogs.sciencemag.org/pipeline/archives/2020/08/17/sinopharms-inactivated-coronavirus-vaccine
5. "We will share our vaccine with the world." Inside the Chinese biotech firm leading the fight against COVID-19. Charlie Campbell. Time, 27 July, 2020. https://time.com/5872081/sinovac-covid19-coronavirus-vaccine-coronavac/

Coronavirus (22) COVID-19 vaccine candidates in clinical trials: inactivated vaccines (b)

Continued from my last blog post.
2. Two inactivated vaccines by Sinopharm Group Co. Ltd.
According to a report from WHO, Sinopharm has two inactivated SARS-CoV-2 vaccines undergoing phase 3 clinical trials.¹ These two vaccines were developed from its biologic research institutes in Beijing (Beijing Institute of Biological Products) and Wuhan (Wuhan institute of Biological Products and Wuhan Institute of Virology*). According to the results from earlier tests, both vaccines look likely to require a booster shot as the strongest antibody response was seen after the third injection.^2,3

One of the vaccines, BBIBP, which was developed by the Beijing subsidiary of Sinopharm, had its development report published in Cell in August.² The report showed that the vaccine was inactivated by β-propiolactone^$ and the final bulk was prepared by adding aluminium hydroxide as an adjuvant.² However, the test result from the phase 1 and phase 2 clinical trials, and the details about the phase 3 trials on BBIBP, are not available to the public.

The other vaccine, which was developed by the Wuhan subsidiary of Sinopharm, is having its phase 3 trials in the United Arab Emirates (UAE).⁴ The trial is being conducted in alliance with the Abu Dhabi Government and Abu Dhabi-based company G42 Healthcare. Abu Dhabi Health Services, SEHA，is managing the trial and has started the project since late June. The trial has a target of 15,000 volunteers across 3 cohorts.⁴ According to a recent report, sites in the UAE have already administered the vaccine to more than 5000 people.⁵ The phase 3 clinical trials of the vaccine have also been expanded to Bahrain (the study involves up to 6,000 volunteers aged over 18 and will last for more than 12 months),⁶ Peru, and Morroco.⁷ Peru is one of the Latin American countries that is hardest hit by the novel coronavirus.

The phase 1 and phase 2 clinical trials of the Wuhan shot were completed in China and the test results have been published in the Journal of the American Medical Association (JAMA). The paper presents results from a 96-subject phase 1 trial that assessed 3 doses (2.5, 5, and 10ug/dose), as well as a 224-subject phase 2 trial, on healthy adults aged between 18-59.³ The shot triggered robust antibody responses in the participants using the 3 doses. However, the authors said in the paper that it is remained unknown if that was sufficient to prevent COVID-19 infection, as the study did not include a comparison using serum samples from patients previously infected with SARS-CoV-2;³ The results in both phases indicated that a longer interval (21 days and 28 days) between the first and second injections produced higher antibody responses compared with a shorter interval schedule (14-day group); the 2 phases of clinical trials also showed that the vaccine candidate is safe to use. There was no notable change in serum CD3+ CD8+ T cells and cytokine levels across the groups in the test. This indicates that the inactivated vaccine was well tolerated. Moreover, although the study found that 15% of 320 participants in the 2 trials experienced adverse reactions, the most common adverse reaction was injection site pain, which occurred in 35 volunteers, followed by fever in 10 volunteers. All adverse reactions were mild, transient, and self-limiting, and did not require any treatment.³

Sinopharm is the largest pharmaceutical company and is state-owned. It recruits more than 1500 subsidiaries, including 6 publicly-listed entities.⁸ The company should be big enough to sustain the development and production of the vaccines for COVID-19. According to the chairman of the company, Liu Jingzhen, the vaccine product could reach the market by the end of the year.⁹ The facility in Beijing and Wuhan should have enough capacity to make more than 200 million doses a year.

The vaccine is expected to cost about US$145 for 2 doses of injection, according to a report in a state-owned media Guangmind Daily.⁹ This price is not cheap at all compared with the shots from other companies.^&

It is interesting to learn that China has already offered both vaccines to employees of some large state-owned companies who plan to travel overseas since June, through the state-owned Assets Supervision and Administration Commission, according to Bloomberg News.¹⁰



*This virology institute has been linked by U.S. Secretary of State Mike Pompeo to “enormous evidence” that it is the source of the global COVID-19 pandemic, a contention denied by Chinese officials.

^$β-propiolactone is carcinogenic but it can be easily removed by vacuum or heating as it is highly volatile.

^& “Moderna, an American vaccine maker, says it will charge US$32 to US$37 per dose of its vaccine. Johnson & Johnson, an American pharmaceutical company, recently struck a deal with the U.S. government, that suggests its vaccine will cost around US$10 per shot. Pfizer, the U.S. pharmaceutical firm, confirmed in July that it would set a price ceiling of US$20 per dose of its potential vaccine. In the UK, AstraZeneca, the British pharmaceutical company, and Oxford University may offer their vaccine candidate for as low as US$3 per injection.” -A Chinese company says its vaccine will be ready by December—but it won’t be cheap. Grady McGregor. Fortune, 22 August, 2020.



References
1. Draft landscape of COVID-19 candidate vaccines. World Health Orgainzation. 20 August 2020. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
2. H. Wang, Y. Zhang, B. Huang, et al. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell, 2020, 182, issue 3, p713-721.
3. S. Xia, K. Duan, and Y. Zhang, et al. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes. Interim analysis of 2 randomized clinical trials. JAMA, August 13, 2020. doi:10.1001/jama.2020.15543
4. China’s Sinopharm launches Phase III trial of Covid-19 vaccine in UAE. Clinical Trials Area. 17th July, 2020. http://clinicaltrialsarena.com/news/sinopharm-covid-vaccine-uae-trial/#:~:text=Share%20Article-,China-based%20pharmaceutical%20company%20Sinopharm%20has%20initiated%20a%20Phase%20III,enter%20a%20Phase%20III%20trial.
5. Coronavirus: What is the vaccine being tested on 5,000 people in Abu Dhabi? The National. https://www.thenational.ae/uae/health/coronavirus-what-is-the-vaccine-being-tested-on-5-000-people-in-abu-dhabi-1.1051051
6. Bahrain starts Phase III trial of Sinopharm’s Covid-19 vaccine. Clinical Trials Arena, 24th August, 2020. https://www.clinicaltrialsarena.com/news/bahrain-vaccine-trial-sinopharm/
7. Peru, Morocco to test China Sinopharm's COVID-19 vaccine in phase 3 trial. CGTN, 22nd August, 2020. https://news.cgtn.com/news/2020-08-20/Peru-to-test-China-Sinopharm-s-COVID-19-vaccine-in-Phase-3-trial-T6YCIZf0I0/index.html
8. Sinopharm Group (Wuhan Institute of Biological Products) and Chinese Academy of Sciences (Wuhan Institute of Virology). Genetic Engineering and Biotechnology News. 18th May, 2020. https://www.genengnews.com/covid-19-candidates/sinopharm-group-wuhan-institute-of-biological-products-and-chinese-academy-of-sciences-wuhan-institute-of-virology/
9. Sinopharm chief says COVID-19 vaccine will cost less than $145 for 2-dose regimen. Angus Liu. Fierce Pharma. August 18, 2020. https://www.fiercepharma.com/vaccines/china-sinopharm-chief-narrows-down-covid-19-vaccine-price-to-within-145-for-2-dose-regimen
10. China offers shots to workers going abroad amid vaccine race. Bloomberg News, 10 June 2020. https://www.bloomberg.com/news/articles/2020-06-10/china-offers-shots-to-workers-going-abroad-amid-vaccine-race