The next step should be based on scientific trial run data

When will the dream come true? 

Until today, about 200 vaccine candidates against Covid-19 are under development, and some have progressed to Phase III clinical trials to receive the green signal in order to vaccinate millions of people around the world, to prevent the virus, now and in the future. This effort could be collaborative or independent, but the common goal is to present the world with a happy face. 

While millions of dollars have been invested for all of the vaccine trials, do we really need more than one vaccine? In fact, there is no need to have even two vaccines when one vaccine works, because our childhood vaccination program is unique for the world and well accepted by the people where same vaccines are given to children all over the world. 

Since Covid-19 is an emerging situation, still it is not clear whether in the end, this vaccine will be added to the routine vaccination program. The one and only demand for a successful new vaccine to enter into this existing standard routine vaccination program requires passing the stringent safety concerns, and showing efficacy in protecting people against developing the diseases. Competition in developing a new Covid-19 vaccine is considered very encouraging; however, one needs to keep in mind that this not a race to reach the finish-line by performing all of the steps of the trials. 

In fact, it is the task that needs to be documented and checked by the experts after finishing each stage and before going to the next. Because of this stringent guideline in place, which is truly for the safety of humans, one cannot skip the preclinical or clinical trials and the relevant experimentations that are needed to evaluate vaccine safety, potency, and the ability to provide long-lasting immunity at best. 

Unfortunately, the current race for the Covid-19 vaccine has turned into a horse-racing event, where announcing news related to new vaccine candidates or estimating the official time to deliver the vaccine have gotten huge priority over core research and scientific activities with the new candidate vaccine. 

This is a bad strategy, which only focused on the increasing of company benefits and shareholders. Instead of engaging with the scientific brainstorming and discussion, making money seems to be the key in this current global Covid-19 crisis. 

What are the phases of trials of a new candidate vaccine?

There are extensive major parts that are critical in the development of a vaccine candidate. In short:

1. Discovery of candidate vaccine -- Among hundreds of vaccine candidates, a couple of candidates will be evaluated in detail to identify one or two candidates that show proper and balanced activation of immunity in laboratory settings.

2. Preclinical trial -- which is generally done in a group of animals to test vaccine doses required to activate balanced immune responses, different routes of administration, side effects or toxicities, targeted immune responses, and finally, challenge the animals with the pathogen to evaluate vaccine efficacy either in a short-term or in a long-term setting. Outcome of these tests must be satisfactory in order to move on to the next step. Most importantly, results from these trials must be documented and submitted for critical review.  

3. Clinical trial -- which is only approved once preclinical testing shows promise and passes all the critical check-points. This is because clinical trials are conducted in humans at different age groups, and primarily aimed at evaluating in healthy adults for safety and immunogenicity together with in-vitro testing, to demonstrate that vaccine-induced immune responses are enough to protect the vaccinated individuals from developing the disease. This human trial has several phases as it moves on, starts recruiting more people in order to evaluate vaccine-induced responses. 

Unfortunately, during this testing, unlike the preclinical trials, there is usually no challenge study to validate the vaccine efficacy. This is why it is very important to perform as many experiments as possible in the laboratory using the volunteer samples to well characterize both the cell mediated and antibody mediated immune responses. The most critical phase is Phase III where 20,000-40,000 volunteers should be vaccinated and followed, their safety and immunity over time -- those likely to demonstrate the long-term adverse effects and protection from getting the disease.  

Who has access to an approved vaccine? What are the front line vaccine candidates?

Obviously, access to an approved vaccine for any country is a number one priority. This is why WHO has a concern under this circumstance, so that countries that are highly affected should get the priority, including health care workers or first-responders. However, the most acute problem in the world is which vaccine candidate would be the best choice for human use. 

Currently, two second-generation vaccine candidates are front runners in phase III trials. National Institutes of Health and Moderna developed mRNA-1273 vaccine that uses the mRNA (messenger RNA) which encodes virus spike S-2P immunogen. The investigational vaccine directs the body’s cells to express the spike protein to elicit a broad immune response. It is already found safe and highly immunogenic in phase I/II trial, and started the phase III clinical trial in July (www.nejm.org/doi/full/10.1056/NEJMoa2022483).  

AstraZeneca and the University of Oxford developed ChAdOx1 nCoV-19 DNA vaccine, which has already shown promising results in human-including antibody and cellular immunity. ChAdOx1 nCoV-19 DNA vaccine has begun phase III clinical trials. These two vaccine candidates have published their research data that are available to the public (www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31604-4/fulltext). 

Chinese company Sinovac, a privately-held Beijing-based company, progressed with an old-fashioned vaccine candidate, which is an inactivated vaccine, and gave two/three different doses of their Covid-19 vaccine to a total of eight rhesus macaques and demonstrated immune responses induced by the vaccination. 

Only preclinical animal study has been published with this inactivated vaccine that required three shots to generate reasonable antibody responses in order to protect the animals from infection (science.sciencemag.org/content/369/6499/77). 

This study did not include analysis of other immunological signatures that are important for protection against infection.

What is our priority with Sinovac’s vaccine trial?

Sinovac’s vaccine is based on inactivated whole virus, a mature vaccine technology that’s also been used to produce vaccines against influenza and polio. However, Western Covid-19 vaccine players are working on next-generation platforms that involve using the DNA or RNA of the novel coronavirus. 

Whether Bangladesh needs to do clinical trials or not, this should be assessed by the merits of the vaccine candidates but not because it is available or there is a fear that if clinical trial is not done, there will be no immediate access to the vaccine. Science must be driving in the decision-making process.   

Inactivated vaccine is an old fashioned platform in the vaccine discovery. There are significant challenges with inactivated vaccine compared with second-generation DNA or RNA-based vaccine candidates. Specifically, the challenge is high to induce proper or targeted immune responses because of thousands of antigenic parts in the vaccine, which are ready to compete soon after vaccination. 

Due to this antigenic competition, it is hard to achieve targeted responses. It also requires adjuvant in most cases, with very (reasonably) high doses of candidate vaccine, but still responses are poor and may not be sufficient to induce long lasting immune responses. Therefore, if targeted, the antigen, let’s say spike protein, will compete with others; it would not be really easy to make the optimal responses when compared with other vaccines either in the mRNA or DNA form. 

To overcome this, inactivated vaccine does need to be given with a high dose and multiple shots, which may induce lots of irrelevant or cross reactive antibodies. Cross-reactive antibodies could be good, but at the same time may lead to antibody-dependent enhancement, or ADE, which is dangerous for the vaccinated individual (Nature Biotechnology volume 38, pages 789–791(2020)). 

Instead of disease protection, ADE effect may enhance virus entry and replication, which can be life-threatening. For example, for the dengue vaccine, the ADE effect was responsible for killing dengue-vaccinated children. Other than dengue, more examples can be given. For instance, SARS and MERS, which are closely related to Covid-19 virus. Notably, the candidate vaccines for SARS and MERS failed to enter into human clinical trials due to the potential ADE effect. 

Data is not available for Sinovac’s vaccine candidates, whether it has been checked for NO ADE effect. Although Sinovac held a press conference to declare sufficient antibody production with no adverse effect to the vaccinated individuals in their Phase I and Phase II trials, the data is not available for critical evaluation.      

Generally, vaccine safety is the number one priority for each country. It is recommended to do vaccine trials in a place where infection rate is high, which gives the opportunity to examine if a candidate vaccine could protect from the disease. However, it is also important to keep in mind that immune responses against Covid-19 are still not completely characterized. 

Recent reports demonstrate the presence of both antibody and T cell mediated responses in the recovered, asymptomatic, and even individuals with no infection history. This changes the initial thought of only antibody-based immunity against Covid-19 infection/vaccination, and now there is demand for the assessment of proposed vaccine candidates extensively. 

Over 90,000 people have recovered from natural infection of Covid-19 in Bangladesh. This is an official count, but the actual count might be several million in Bangladesh, because of no proper tracking of the cases, which does need extensive testing and monitoring. In this situation, learning the individual’s immunity that has been developed after natural infection should be the number one priority. The major point is -- why is this not getting any attention? 

Because once we know more about the immunity that is developed in the recovered persons and how long this immunity is lasting and what immune compartments are being activated, we will have a clear idea to make a comparison with any proposed candidate vaccine-induced immune responses. Obviously, natural infection and recovery might have full-length immunity than the inactivated vaccine. Sinovac vaccine will be given to thousands of people in Bangladesh and if they are not checked for prior Covid-19 immunity (due to natural infection/exposure), how will this vaccine-induced immunity have efficacy? 

Conclusion

Inactivated vaccine may not be a very good choice at the end, and Bangladesh does not need to give green signal to this Phase III trial simply due to the lack of proper scientific data. As of today, WHO reports that 26 vaccine candidates are in various stages of human trials. 

Bangladesh should encourage clinical trials for Covid-19 candidate vaccines that show scientifically sound candidate vaccine discovery strategies, well-performed preclinical studies, and peer-reviewed published manuscripts on already performed human clinical trials. While many other vaccine candidates show solid scientific data, why not make an effort to have those trial runs in Bangladesh? 

For example, India has given green signal to initiate phase III trials in the Indian population with Oxford-AstraZenneca vaccine candidate. Bangladesh cannot start the Phase III clinical trial with the vaccine candidate of Sinovac based on just a published pre-clinical study which has been of questionable quality. 

Sinovac must publish its Phase I and Phase II human trial data in order to proceed with the possible Phase III trial in Bangladesh. 

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



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