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More on COVID-19 vaccine Phase III trials: where are they being done and does that affect FDA approval chances?

2020-09-09
Muscat Avenue in fall– plum trees on left, peach trees on right. From personal photo album.

Moderna and the National Institutes of Health (NIH) are conducting Phase III clinical trials of its vaccine, based on mRNA (a new technology for vaccines) at 89 sites in the USA. 30,000 volunteers will be recruited. The beginning of Phase III was announced on July 27. On August 11, the federal government announced a further $1.5 billion subsidy to Moderna for the vaccine.

In June, the Food and Drug Administration (FDA) announced its criteria for efficacy: the vaccine would have to protect at least 50% of people to be considered effective. They did not say whether that meant that “protection” meant that people would not be infected with SARS-COV-2 or, alternatively, that they would not have symptoms of COVID-19 even if they did get infected. It is possible that a vaccine could protect against symptoms despite infection– and an average of 40% of infected people do not display symptoms anyway.

BioNTech of Germany, Pfizer, and Fosun Pharma of China have been conducting combined Phase II and Phase III trials on an mRNA vaccine that they call BNT162b2 since July 27. These trials are being conducted in the USA and “other countries including Argentina, Brazil, and Germany.” Again, these trials are recruiting 30,000 volunteers, which seems to be a standard number.

The chief executive at Pfizer stated in September that they would know if the vaccine works as soon as October of this year. The federal government has awarded Pfizer $1.9 billion for 100 million doses to be delivered by December (assuming the vaccine works) and Japan has made a deal for 120 million more doses.

CanSino Biologics is working on Phase III trials of its vaccine, called Ad5, using an adenovirus as a vector. The adenovirus is considered nonpathogenic (does not cause disease symptoms.) The vaccine is being developed in partnership with the Chinese Army’s Institute of Biology in its Academy of Military Medical Sciences and it was approved as a “specially needed drug” temporarily on June 25. It is apparently already being used by the Chinese military. The trials are being conducted, since August 9, in Saudi Arabia and Pakistan.

The Gamaleya Research Institute of the Russian Ministry of Health is working on a vaccine that uses two different adenovirus vectors, called Sputnik V. This vaccine was conditionally approved on August 11, and since then Phase III trials have begun and have been expanded to 40,000 “volunteers.” Phase I/II results were published September 4, and the Phase III trials are apparently all being conducted in Russia.

AstraZeneca and Oxford have been developing a vaccine based on a chimpanzee adenovirus, called ChAdOx1. Phase III trials were temporarily halted a few days ago because a volunteer had an unexpectedly severe reaction; it is still not known whether the reaction was due to the vaccine itself. According to the New York Times, “Phase 2/3 trials [are underway] in England and India, as well as Phase 3 trials in Brazil, South Africa, and the [USA].” Indian facilities have already manufactured millions of doses for use in trials. The European Union has also made a deal to accept 400 million doses if the trials turn out well.

Sinovac Biotech is testing an inactivated vaccine under Phase III protocols in Brazil and Indonesia. The Chinese government has given this vaccine a limited emergency approval as well, although there was no information as to who was actually receiving it. The Indonesian government has made a deal to get 40 million doses by March 2021.

Sinopharm and the Wuhan Institute of Biologic Products are developing an inactivated vaccine which is in Phase III testing in the United Arab Emirates, Peru, and Morocco since July and August. The UAE trials are enrolling 5,000 volunteers for this vaccine.

Sinopharm and the Beijing Institute of Biological Products are testing another inactivated vaccine. Phase III tests are underway in the United Arab Emirates, using 5,000 volunteers.

One of the two Sinopharm vaccines has also gotten limited emergency approval from the Chinese government; it is unclear whether it is the Beijing or the Wuhan product. It is also unclear who is receiving the emergency vaccine, but it may be front-line health workers and/or soldiers.

For completeness, we should also mention an Australian trial of the Bacillus Calmette-Guerin (BCG) vaccine, which was developed to protect against tuberculosis and has been in use since 1921. The BCG product does not fully protect against tuberculosis, although it apparently considerably improves physiological defenses against this disease. BCG also provides variable protection against other mycobacteria (tuberculosis is a mycobacterium), leprosy, and even against overall mortality in low-income countries as well as against type I diabetes mellitus (under study.)

BCG has been evaluated against COVID-19 in Rhode Island (see this study) and is currently under Phase III trials in health-care workers in Australia and Netherlands. It is also being tested in Greece.

Most of the above information comes from the New York Times interactive article on vaccines in development.

The significance of the testing locations for these vaccines is that only trials in the USA qualify for FDA approval under normal circumstances. Certainly, the Russian and Chinese vaccines are unlikely to be considered here in the current political climate. Whether the location of Phase III trials matters for the other vaccines is a matter for debate.

An issue that should be recognized, however, is that the US federal executive department, under presidential orders, has refused to participate in the global alliance of more than 170 countries that is working to develop vaccines against COVID-19. The president claims his reason is that the participation of the World Health Organization (WHO) in this alliance (it is also supported by the Global Vaccine Alliance (GAVI), an organization started by Bill Gates to produce vaccines for poor countries, among others) somehow taints this global alliance. I do not support this “reasoning” and feel that it is more in the nature of a personal vendetta against WHO, which the president accuses of being beholden to China.

The financial support of the US government for the Moderna and Pfizer vaccines suggests that these will be the chosen ones for the US, assuming they get positive results. The AstraZeneca/Oxford vaccine is the only other one that is being tested in the US.

Most of the vaccines used in the US before this pandemic are produced by four companies: Aventis Pasteur, GlaxoSmithKline (GSK), Merck, and Wyeth. Of these, only GSK (in partnership with Sanofi) is anywhere near a vaccine– with US government support for 100 million doses– and their Phase III study will not begin until the end of this year. The vaccine they are working on is a recombinant protein-adjuvant type, a traditional route. GSK is also in preliminary work with Translate Bio to develop an mRNA-based vaccine. See this article for information on GSK, Sanofi, and Translate Bio.

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