Sinovac’s Covid-19 vaccine shows great promise

A number of articles recently published in the media have questioned the merits of the Sinovac's inactivated SARS-CoV-2 (Covid-19) vaccine and whether the government of Bangladesh should now approve a Phase III trial of the vaccine to determine how well it protects Bangladeshi adults against SARS-CoV-2. Many of the published negative comments are unfounded. Here we hope to set the record straight and alleviate any reservations the government may have in approving the proposed Phase III trial.

Misleading assertions

The Sinovac vaccine, which consists of fully inactivated SARS-CoV-2 virus, in fact shows great promise. This vaccine has already received extensive testing in animals, showing it to be safe, to induce robust anti-SARS-CoV-2 immune responses, and, very importantly, to protect vaccinated primates against SARS-CoV-2 disease when they are experimentally challenged with fully virulent SARS-CoV-2 virus. In addition, the vaccine has been administered to hundreds of Chinese adults under strict experimental protocols, demonstrating that it is safe and induces serum antibody responses that neutralise (e.g. render it harmless) the SARS-CoV-2 virus.

One false assertion has been that the Sinovac vaccine has not induced neutralising antibodies against SARS-CoV-2. In fact, the Sinovac vaccine, when given in two doses, induced virus-neutralising antibodies in the serum of over 90 percent of vaccinated Chinese adults. It is important to recognise that although we think such serum antibodies are relevant to protection against SARS-CoV-2 disease in humans, this is still just an assumption based on experience with non-SARS-CoV-2 viral infections. Similar misleading statements have been made about "poor" T cell responses to the Sinovac vaccine. In fact, the Sinovac vaccine is documented to elicit T cell immune responses, but here too we currently lack hard scientific data on how relevant, if at all, such responses are to the prevention of SARS-CoV-2 infection of humans.

Another assertion has been that the vaccine may actually worsen SARS-CoV-2 disease through a phenomenon called "immune enhancement". In fact, immune enhancement is a potential concern for all SARS-CoV-2 vaccine candidates, regardless of their production technology, and the Food and Drug Administration (FDA) of the US is requiring that all SARS-CoV-2 vaccines be evaluated for this possible side-effect in Phase III clinical trials in humans. All trials of the Sinovac vaccine are following this guidance. That said, the primate SARS-CoV-2 challenge studies conducted with the Sinovac SARS-CoV-2 vaccine revealed no evidence of disease enhancement in the challenged animals.

A third assertion has been that the results of the studies of the Sinovac vaccine have not been subjected to proper review. This is patently false. The results for the preclinical studies of the vaccine in animals have appeared in one of the world's most prestigious journals, Science. Results for Phase I and II studies have been submitted for publication, and are available as a prepublication online in medRxiv. Importantly, all of these data have been carefully reviewed by the Ethical and Research review committees at the icddr,b and by the Bangladesh Medical Research Council, and have been submitted for review to the Directorate General of Drug Administration (DGDA) of Bangladesh. Moreover, approval for human trials of the Sinovac vaccine has been obtained after review of all preclinical and clinical data by the WHO-approved Brazilian National Regulatory Authority.

A fourth assertion has been that the Sinovac vaccine uses the "outdated" technology of inactivated whole viruses, and that such "next generation" technologies as mRNA vaccines (NIH/Moderna) and live adenovirus vaccines into which Covid genes are introduced (Oxford/Astra Zeneca) are preferable. There is no scientific basis for this assertion. Killed virus technologies are currently used for effective, licensed vaccines against influenza and polio. In contrast, no human vaccine using mRNA or adenovirus vector technology has ever been licensed on the basis of well-conducted Phase III trials, and several vaccine candidates against other infectious diseases using the adenovirus vector technology have failed to protect humans. This is not to say that these newer approaches will fail, but rather that SARS-CoV-2 vaccines based on the well-established approach used by Sinovac, as well as on the newer approaches, should all undergo evaluation in human Phase III trials if supported by preclinical evidence and human Phase I-II study data showing safety and immunogenicity—as is the case for the Sinovac vaccine.

Planned Phase III trial

Based on the very promising results of preclinical studies in animals and human studies in Chinese adults for the Sinovac SARS-CoV-2 vaccine, Sinovac now plans to conduct Phase III, individually randomised, double-blind, placebo-controlled trials in order to determine the safety and efficacy of the vaccine against human SARS-CoV-2 disease when tested in adults in Brazil, Saudi Arabia, Turkey, Chile, Indonesia and Bangladesh. The trials in Brazil have already commenced. These trials have been designed to ensure that results will meet the highest regulatory standards for vaccine licensure. It is critical that these trials be conducted in multiple countries and differing populations as the epidemiology of SARS-CoV-2 differs from population to population, and different human populations may respond differently to any given vaccine.

In Bangladesh, we plan to enrol 4,200 literate healthcare workers (doctors, nurses, ward attendants) who have not yet been infected by SARS-CoV-2, from seven hospitals in metropolitan Dhaka that are caring for SARS-CoV-2 patients. Participants will be randomised at a 1:1 ratio to receive two doses of either the Sinovac vaccine or a placebo via intramuscular injection. Intensive follow-up of all participants will be conducted to detect adverse reactions to the vaccine as well as SARS-CoV-2 disease. Appropriate management will be provided for all illnesses of the participants. Although all participants will be followed in this manner for a year after dosing—to make sure that the vaccine is safe and does not cause immunological enhancement of SARS-CoV-2 disease—we expect that enough SARS-CoV-2 cases will have occurred within six months of dosing to draw conclusions about the ability of the vaccine to protect against SARS-CoV-2 disease.

Benefit to Bangladesh and to the world

An effective vaccine against SARS-CoV-2 will save countless lives in Bangladesh and around the world. If the Phase III trial of the Sinovac vaccine in Bangladesh demonstrates the vaccine to be safe and protective, Sinovac has agreed to provide over 110,000 free vaccine doses for the nation. And more importantly, Sinovac has committed to transfer the technology for production of the vaccine, as well as bulk vaccine, to a qualified Bangladeshi producer at a discounted price to meet the needs of the larger population of Bangladesh. We believe that this trial, if successful, will be a great credit to the people and government of Bangladesh. Moreover, it will directly benefit the citizens of Bangladesh, and the world. But time is of the essence, and we thus urge the government of Bangladesh to give the proposed trial its approval and full support.

The statement has been jointly given by Prof John D Clemens, MD Executive Director, icddr,b, Prof Jan Holmgren, MD, PhD, University of Goteborg, Sweden, Dr K Zaman, MBBS, MPH, PhD, Senior Scientist, icddr,b, Dr Firdausi Qadri, PhD, Senior Scientist, icddr,b, and Prof Allen Ross, MD, PhD, Senior Director, Infectious Diseases Division, icddr,b.