C-19 vaccine trial in Bangladesh: Is inactivated vaccine viable?
More than 200 vaccine candidates against COVID-19 is currently under development and some of them have been progressed to Phase III clinical trials. If one becomes successful, there will be a great relief for the entire world. However, the biggest challenge would be then which country or who the people will get preference to be vaccinated. This does require a consensus among the countries under WHO. The effort to make a vaccine is either collaborative or independent, but the common goal is to present the world a 'happy face'.
Do we really need more than one vaccine? 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 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. Unfortunately, the current race for COVID-19 vaccine has turned into a horse racing event where announcing news related to new vaccine candidate or estimating the official time to deliver the vaccine have got huge priority over core research and scientific activities with the new candidate vaccine.
What are the phases of trials of a new candidate vaccine?
There are extensive major parts that are critical in 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 a balanced immune responses, different route 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. Most importantly, results from these trials must be documented and submitted for critical review.
3. Clinical trial-which is only approved to do once preclinical testing shows promise and passes all the critical check-points. 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. The most critical phase is the Phase III where 20000-40000 volunteers should be vaccinated and followed their safety and immunity over time, 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, 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 phase III clinical trial in July.
AstraZeneca and University of Oxford developed ChAdOx1 nCoV-19 DNA vaccine which already showed 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 public.
Chinese company Sinovac, a privately owned Beijing-based company, progressed with an old-fashioned vaccine candidate, which is an inactivated vaccine, 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. This study did not include analysis of other immunological signatures that are important for protection against infection.
Sinovac's vaccine trial in Bangladesh: is this a right choice for us?
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 a clinical trial or not should be assessed by the merits of the vaccine candidates.
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 so high to induce proper or targeted immune response 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 reasonably very high doses of candidate vaccine but still responses are poor and may not be sufficient to induce long lasting immune responses.
Therefore, if targeted antigen, let's say spike protein, will compete with others, it would not be really easy to make the optimal response 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. Instead of disease protection, ADE effect may enhance virus entry and replication, which can be life-threatening.
Notably, the candidate vaccines for SARS and MERS failed to enter into human clinical trials due to the potential ADE effect. Data are not available for Sinovac's vaccine candidate whether it has been checked for 'NO ADE' effect. Although Sinovac made 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 are not available for critical evaluation.
Generally, vaccine safety is the number one priority for each country. It is recommended to do vaccine trial 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 demonstrated 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 demand the assessment of proposed vaccine candidates extensively.
Inactivated vaccine may not be a very good choice and Bangladesh does not need to give green signal to this phase III trial simply due to the lack of proper scientific data. BD 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 to make an effort to have those trials run in Bangladesh?
Bangladesh cannot start the Phase III clinical trial with the vaccine candidate of Sinovac only based on just a published preclinical study which has been of questionable quality. Sinovac must publish its Phase I and Phase II human trials data in order to proceed with the possible Phase III trial in Bangladesh.
Dr Jubayer Rahman & Dr Md Shamsul Alam are Researcher of National Institutes of Health, USA. Dr Reza Karim, WHO-Utrecht Center of Excellence for Affordable Biotherapeutics, Netherlands.