The selection of a vaccine candidate should be entirely based on the scientific merits
Vaccines can save lives, but they can also kill healthy people if safety is not rigorously ensured. As researchers with relevant expertise, we raised our concern about the safety of the Sinovac vaccine trial in Bangladesh.
The daily Dhaka Tribune recently published our opinion pieces -- “Is Sinovac’s inactivated vaccine candidate promising?” and “No light at the end of this tunnel?.”
To our surprise, it appears that one reputed research organization, icddr,b, has taken our valid scientific comments on the safety aspects of the candidate vaccine institutionally without referring to our Op-Ed articles, and released a joint statement in mainstream print media -- “Sinovac’s Covid-19 vaccine shows great promise” (The Daily Star, August 22, 2020), and the Bengali version of the statement was published in the Prothom Alo the next day (August 23, 2020).
In the joint statement, the executive director of icddr,b and other scientists unexpectedly labelled our opinions as “false assertion” and “patently false.” The joint-statement also mentioned: “Many of the published negative comments are unfounded.” This is an unwanted reaction from a reputed organization like icddr,b.
In perspective, we refute the misleading assertions made by those icddr,b scientists in a point-by-point scientific rebuttal.
It is important to mention that there is a conflict of interest here since icddr,b has made a contract with Sinovac Company Ltd for a vaccine trial as a Contract Research Organization (CRO) in Bangladesh. Here are our points-by-point responses.
“One false assertion has been that the Sinovac vaccine has not induced neutralizing antibodies against SARS-CoV-2. In fact, the Sinovac vaccine, when given in two doses, induced virus-neutralizing antibodies in the serum of over 90% of vaccinated Chinese adults.” (Daily Star)
It seems that those icddr,b scientists are biased (non-scientifically) to this vaccine candidate, which induces poor antibody titers (neutralizing antibody levels induced by Sinova’s candidate vaccine are much lower compared to convalescent sera (23.8 to 65.4 by vaccination compared to 163.7 in convalescent sera), even significantly decreased in the oldest group of individuals (59 years old). Clearly, “no” T cell responses have been reported.
Most importantly, antibody responses alone are just not enough. For many years, the focus of prophylactic vaccines was to elicit neutralizing antibodies, but it has become increasingly evident that T cell-mediated immunity plays a central role in controlling future viral infections.
In fact, antibody titers even in recovered Covid-19 patients wane after some time. It is therefore urgently necessary to take the role of both the antibody and the T cell mediated responses into account.
Most of the front line vaccine candidates (mRNA1273 or Oxford vaccine ChAdox1) either completed animal or human trials focused on both antibody and memory T cell responses. B cells that make antibodies are critically dependent on helper T cells.
Notably, another Chinese vaccine manufacturer, CanSino Biologics, was able to show neutralizing antibody response in a similar range as convalescent sera.
“Another assertion has been that the vaccine may actually worsen SARS-CoV-2 disease through a phenomenon called “immune enhancement”… 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.” (Daily Star)
Antibody-dependent enhancement (ADE) is a big concern in the vaccine field. The chances of inducing ADE could be even higher when unwanted antibodies are generated after vaccination. This is one of the reasons why second-generation vaccine candidates are more focused on spike protein only.
Moreover, those candidate vaccine trials are also undergoing rigorous testing to find out if there is any ADE effect. Sinovac’s inactivated vaccine candidate is a whole virus but inactivated form which potentially induces lots of irrelevant cross-reactive antibodies.
For instance, the Sinovac candidate vaccine not only induces antibodies against the Spike-specific, receptor-binding domain (RBD), but also induces antibodies against other parts of viral protein (nucleocapsid) which might be dangerous because of immune enhancement.
Sinovac claimed in their published paper that other antibodies are not protective and could only be related with clinical outcomes of the patient. They cited one article to support this statement.
If this is true, indeed the Sinovac vaccine may pose higher risk for humans with antibody-dependent immune enhancement because of nucleocapsid-specific antibodies that have been reported in “Science” journal. We also want to stress that it is impossible to show the lack of ADE from Sinovac’s pre-publication of a Phase II clinical trial data as ADE was not included in any outcome measures. Therefore, icddr,b scientists strongly advocating that Sinovac’s vaccine candidate is “safe” are doing so prematurely.
“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.” (Daily Star)
Sinovac’s preclinical data has been published in “Science” journal. The data at the preclinical level (animal model) only showed neutralizing antibody responses, but failed to induce T cell responses. Where has Sinovac shown that its vaccine can elicit T cell immune responses?
In the pre-publication online in medRxiv, Sinovac has not shown any data whatsoever with regard to T cell response. In other words, T cell responses in the human Phase II trial are completely missing.
Moreover, in the preclinical (animal) studies, Sinovac showed T cell data but there was no significant difference in T cell-mediated immunity among placebo or vaccinated animals.
Even after giving vaccines of 1.5µg/dose or even 6µg/dose, Sinovac did not find significant differences in CD3+, CD4+ and CD8+ cells and also no significant differences in TNF-α, IFN-γ, and IL-2 production among placebo or vaccinated animals.
How then could the icddr,b scientists say: “The Sinovac vaccine is documented to elicit T cell immune responses?” This is absolutely a misleading and false statement.
“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.” (Daily Star)
Sinovac’s vaccine candidate is an inactivated vaccine which has undergone many passages (P1-P10) in the laboratory during the inactivation process. As part of this extensive process to make sure the virus is fully inactivated, Sinovac vaccine candidates acquired at least two mutations, though Sinovac claimed those mutations were not in the spike protein.
But still, this old fashioned platform poses the risk of introducing new mutations which could lead to either acquiring side effects or losing the potency. To avoid such unwanted problems, second-generation vaccine candidates are codon optimized, which makes spike protein more stable and allows the immune system to recognize efficiently to generate robust immunity.
As a matter of fact, both Moderna/NIH and Oxford/AstraZeneca vaccine candidates are examples of such candidates that induce both antibody and T cell responses as evidenced by the preclinical to clinical trial published in NEJM and Lancet journals respectively.
The manufacturing processes to develop vaccines are highly complex. Vaccines are produced by bio-manufacturing processes where a tiny variation in the manufacturing processes can impact the quality of the vaccine tremendously.
Ample examples can be given where a biologic drug met the regulatory requirements in every stage of drug development, including discovery research, preclinical, and clinical development, however, due to a tiny inconsistency in the manufacturing process, that biologic drug failed to receive approval from the European Medicines Agency (EMA) or US FDA.
Surprisingly, Sinovac in its pre-publication 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 is extremely astonishing to see that Sinovac has 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?
Is this the reason why Sinovac does not publish its Phase I trial data on 144 participants (NCT04352608)? More importantly, we would be pleased to learn from those icddr,b scientists if they can show us a single example where a vaccine received marketing authorization approval by the EMA or US FDA, where two different qualities of vaccine candidates were used in the same clinical trial.
It should be noted that just two years ago, in 2018, China had a vaccine scandal where the Chinese Changsheng Biotech company administered substandard DPT (diphtheria, pertussis, and tetanus) vaccine to 215,184 children. At the same time, another Chinese company named Wuhan Institute of Biological Products sold 400,520 substandard DPT vaccines in Hubei and Chongqing.
For this scandal, Chinese authorities detained 15 people, including the chairman of Changsheng Biotech. That caused huge chaos in the scientific community, and the top scientific journals like The Lancet, Nature, and nonscientific press like The New York Times and CNN reported on it.
Nonetheless, on July 31, the Nature journal published a concerning editorial on the Chinese vaccine, written by David Cyranoski, entitled “China’s coronavirus vaccines are leaping ahead -- but face challenges as virus wanes.”
Surprisingly, icddr,b found the Sinovac vaccine very effective without potential solid ground.
None of the front-line vaccine candidates are made by the Bangladeshi scientists; however, it is high time to evaluate carefully the scientific data that has been generated for each of the candidate vaccines before making a selection of a particular one for conducting Phase III trial.
The selection of a vaccine candidate should be entirely based on the scientific merits, not because of any potential benefits that someone is offering or due to personal interest.
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.