OP-ED: No light at the end of this tunnel?

On August 10, 2020, Sinovac published its Phase II human trial data on medRxiv.org, the preprint server for health science (https://www.medrxiv.org/intent/10.1101/2020.07.31.20161216v1).

The trial had been conducted in China, and was a double-blind, randomized, and placebo-controlled trial (trial ID NCT04352608). Sinovac inactivated vaccine was given to 600 healthy volunteers (adults aged 18-59 years) as part of Phase II clinical trial to monitor vaccine safety and immunogenicity.

Immunogenicity data indicates how effective the vaccine could be. In the Phase II trial, a vaccine candidate needs to satisfy both the safety and immunogenicity. In this regard, Sinovac’s vaccine only met the short-term safety criteria but could not induce optimal immune responses. Moreover, the safety of this vaccine trial needs to be examined in a long-term setting.

In order for a vaccine to be effective, the vaccine needs to induce a proper, balanced, and long-lasting immune response. Vaccines need to activate both the antibody-mediated immune responses as well as T cell-mediated immune responses.

There are a number of key scientific peer-reviewed articles that recently emphasized the Covid-19 specific T cell responses that were found in Covid-19 patients when recovered, as well as asymptomatic individuals. These findings underscore the importance of T cell responses beside the antibody responses in order for a potential Covid-19 vaccine to be effective in preventing the disease.

Antibodies play a critical role in protecting a vaccinated individual. After vaccination, the vaccinated subjects must produce the so called neutralizing antibodies which, upon future encounter with the same virus, our immune system will neutralize, protecting us from the infection.

To induce antibody responses, which come from B cells, T cells need help from B cells to generate such antibodies. In this direction, T cells need to be activated and should form memory for future attack by the virus. This is exactly the reason why scientists in the vaccine field constantly urge to check if a new vaccine candidate could induce enough T cell responses.

Sinovac shows that the vaccinated subjects were able to mount neutralizing antibodies. However, Sinovac mentions in their manuscript that the level of the neutralizing antibody in vaccinated individuals is lower than the serum of convalescent patients tested by the same method in the same laboratory. Sinovac mentions that the neutralizing antibody levels range from 23.8 to 65.4 compared to 163.7 in a convalescent serum. This difference is huge.

Although Sinovac’s vaccine candidate induced comparable antibody responses in the animal model, data from the human trial seems incompetent to proceed with the Phase III trials with the same doses and vaccination protocols.

Notably, we may look into the data of another Chinese vaccine manufacturer namely CanSino Biologics (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext); this vaccine was able to show neutralizing antibody response in similar ranges as convalescent serum. Therefore, Sinovac data indicate that their candidate vaccine is not potent in inducing a proper level of neutralizing antibodies in vaccinated individuals.

Most importantly, Sinovac has not reported any T cell responses in the vaccinated individuals in this Phase II trial. With regard to T cell responses, mRNA1273, vaccine candidate of Moderna/NIH; ChAdOx1, vaccine candidate of Oxford/AstraZenneca; and the vaccine candidate of CanSino’s among others showed both antibody and T cell-mediated immune responses in their respective Phase-I/II human trials.

However, Sinovac fails to show such T cell-mediated immune response in the vaccinated subjects in their preprint article. Importantly, it is well-established in the scientific community that the inactivated virus vaccine, the platform of vaccination technology Sinovac uses is old-fashioned and such vaccinations require higher doses and multiple boosters to induce desired immune responses if that is at all possible.

These repeated attempts could end up with non-specific immunity that can be life-threatening for the vaccinated individuals. Non-specific immunity could easily take over control once the specific immunity wanes, and can help the virus to infect the vaccinated subjects more potently, which is termed as antibody-mediated enhancement (ADE).

Many examples can be given for how deadly ADE can be even in killing the vaccinated persons. Moreover, the inactivated vaccine platform that Sinovac uses is scientifically known that such vaccines fail to mount a proper T cell-mediated immunity, therefore, Sinova’s failure to show such cell-mediated immunity is expected and not very surprising. 

The manufacturing processes to develop vaccines are highly complex. For instance, scientists compare manufacturing of paracetamol or antibiotics to manufacturing a bike, whereas the manufacturing of a vaccine is like that of a SpaceX shuttle.

Vaccines are produced by bio-manufacturing processes where a tiny variation in the manufacturing processes can impact the quality of the vaccine tremendously. Sinovac in its preprint manuscript mentioned that the company used a vaccine candidate in their Phase I study, which was of different quality as the one used in their Phase II trial.

It was of the utmost surprise to see that Sinovac had started its Phase I and Phase II studies before properly finalizing and validating the manufacturing process of highly complex vaccine development. This follows another question, how would Sinovac compare the data of its Phase I and Phase II trials as two different qualities of vaccine candidates were used? 

Conclusion

Bangladesh should not approve the trial of Sinovac’s vaccine candidate as Sinovac’s preclinical and Phase II clinical study data are not of satisfactory quality in mounting a proper and balanced immune response. Twenty-eight candidate vaccines have so far entered various phases of human trials and Bangladesh should start clinical trials with those vaccine candidates that show sound scientific data to protect human lives.

Dr Rezaul Karim is an immunologist and project lead at WHO-Utrecht Centre of Excellence for Affordable Biotherapeutics, the Netherlands. Dr Jubayer Rahman and Dr Md Shamsul Alam are immunologists working at the National Institutes of Health, USA.