As COVID-19 continues to snowball into a massive health and economic concern, the world is anxiously anticipating a vaccine. While Russia’s vaccine was approved in August, several biopharma giants worldwide have progressed their candidates to Phase III evaluations in a rush to deliver them at an unprecedented speed. Yet, “vaccine development is one thing, vaccination is another,” says Prof. Han van den Bosch, a seasoned veteran in the vaccine development space. Dr. van den Bosch is an emeritus professor of “International Public Health” at the Vrije Universiteit in Amsterdam. He has held top management posts in the industry in global R&D and has been instrumental in developing vaccines for various diseases. We invited him for a discussion to obtain expert opinions on a range of topics pertaining to COVID-19 vaccines.
The COVID-19 pandemic has affected close to 45 million people around the globe, with a total of 1.1 million deaths. With vaccines, antivirals, and repurposed drugs still under development, this dismal trend is expected to continue. Vaccine development is met with numerous stumbling blocks, which becomes more exaggerated due to time constraints. Hence, the approval of Russia’s Sputnik-V even before completing the Phase III trials has come as a huge surprise to many. While the quick pace of vaccine development is encouraging, one must view that with guarded optimism. Recently, the clinical trials of AstraZeneca and Johnson & Johnson, the frontrunners in the vaccine race, were temporarily paused due to safety concerns and resumed after regulatory examinations. So, it is imperative to ponder about the challenges in vaccine development, including its prolonged timeline. Are premature approvals justified under an emergency, or is it dangerous? We interviewed Prof. Han van den Bosch, an experienced professional in the field, to get some answers.
Challenges Pertaining to COVID-19 Vaccine
Dr. van den Bosch agreed that there are several challenges to developing a vaccine for COVID-19. However, the major one is to get a safe and efficacious candidate to the public as quickly as possible. Considering the circumstances, he feels that we have progressed with great speed, and so far, we’re doing exceptionally well in terms of development. Yet, “vaccine development is one thing; vaccination is another,” he cautioned.
He explained it further by pointing out that through years of implementing rigorous science and following the regulatory pathways to get to the market, we have learned exactly how to develop vaccines. However, he is more concerned about producing sufficient vaccine doses and conducting vaccination programs across several countries. Considering we have a world population of eight billion people who require at least two vaccination doses to ensure full protection, this amounts to a gigantic aggregate of approximately 15 billion vaccine doses.
The scale is unprecedented, and we also have to deal with the challenge of administering these vaccinations without disturbing the other standard childhood or adult vaccination programs in place. “We cannot have a situation where people are now protected against COVID, but they fell ill from polio, measles, diphtheria, or tetanus,” he warned.
Rapid Progress In Vaccine Development
Previously, scientists had gathered extensive data on the causative viruses of Polio, Hepatitis A, or even Ebola before the development of their respective vaccines. In contrast, the COVID-19 vaccine development coincides with SARS-CoV-2 research. When we asked Dr. van den Bosch whether the pandemic took vaccine developers by surprise, he did not completely agree with that assessment. Instead, he stressed that SARS-CoV-2 is still a coronavirus, and scientists had amassed immense knowledge about other coronaviruses, including SARS-CoV-1 and MERS-CoV, to get the ball rolling quickly.
“We had the complete sequence of the SARS-CoV-2 genome sent over from China very early. We knew exactly what to pick as a target, which was either the spike protein or its receptor-binding domain. Besides, we knew about its stability and structure. We only had to compare it with SARS and MERS, and we could immediately start working on those building blocks and develop a vaccine. That’s what happened with some of the front runners of the vaccine race like the Adeno-vectored vaccines from Oxford/AstraZeneca and Johnson & Johnson,” he said.
Oligonucleotides Versus Traditional Vaccines
We then moved to the topic of rapidly producible oligonucleotide vaccine candidates such as the ones from Moderna and Pfizer & BioNTech, Dr. van den Bosch termed the advent of oligonucleotide vaccines as a new era, and one has to wait to judge their performance. He reflected that such dramatic innovations need to be ascertained, whether they are affordable in a pandemic situation. Fortunately, we have other options in the reckoning, such as protein and inactivated vaccines, the technologies of which are backed by relatively established technologies.
He agreed that the production is easier with oligonucleotide vaccines, but we have no experience with the large-scale application. The same is true for traditionally produced vaccines, but we lack experience with candidates produced with newer technologies.
“Another important factor is that oligonucleotide vaccines are heat-labile and unstable. I was shocked to learn that some of the vaccines have to be kept at temperatures ranging from minus 20 to minus 70 degrees, which is a logistical nightmare. Perhaps developed countries such as the US can handle it, but it is a far cry for developing and underdeveloped countries. There are some veterinary vaccines today that are stored in frozen temperatures around the world, but it is only possible because of the infrastructure we built over the years,” he said.
He explained that basically, we have eight different technologies employed in the production of COVID-19 vaccines, which we have perfected over time. He personally favors the well-defined subunit vaccines and the ones developed by proven technologies.
“This is not going to be a normal vaccination program like we have done so far. Even with Ebola, it was a challenge, but the number of people to be vaccinated was limited. Vaccinating the complete world population is a colossal task, and minor adverse effects will immediately be enlarged. Those setbacks are expected at this scale, but at least the science should be sound, and we must follow all the safety and efficacy guidelines formulated by agencies like the FDA, EMA, and the WHO,” he quipped.
Vaccine Development Timeline
Vaccine development starts with discovery and lead optimization, which usually takes a couple of years. Fortunately, in the case of COVID-19, we already knew exactly what the target should be. Except for inactivated or live attenuated vaccines, the rest of them, like oligonucleotide, protein, or subunit vaccines, are all targeting the spike protein.
Once the target product profile (TPP) is established, a vaccine is on its way towards Phase I clinical trial, which primarily aims for safety in humans. However, a couple of animal toxicity studies need to be performed first. Companies are required to follow strict guidelines for toxicology to prove safety and efficacy in preclinical models. It’s beneficial to have challenge models in animals like non-human primates, hamsters, ferrets, or transgenic mice, which help determine toxicity and efficacy. A Phase I trial typically comprises around a hundred people. Besides estimating the safety, the trial also monitors the immunogenicity levels of the subjects.
Phase II typically enrolls a larger cohort of people from different age groups. It primarily assesses immunogenicity and dosage to determine how much antigen content is required to elicit a protective immune response. Several key questions, such as the inclusion of women of childbearing age or immunocompromised patients, are addressed in this stage. So, in Phase II, there is still room for some experimentation.
Phase III clinical trial is most important because it is placebo-controlled, and it aims to prove safety and clinical effectiveness in a larger set of participants. This is difficult because there are several challenges, such as long-term monitoring, finding appropriate trial locations where the disease is still prevalent, and estimating how many participants might experience adverse events.
“In the case of COVID-19, the candidates that are currently in Phase III trials have enrolled between 30,000 to 60,0000 volunteers. In emergency situations such as this, Phase II trials are initiated even before the completion of Phase I, and a rolling-arms design is put in place to allow the addition of extra arms later in the trial. Similarly, Phase II would still be ongoing while a company embarks on Phase III. Besides, participants have to be followed with booster vaccinations and long-term safety monitoring, and that explains why it takes a long time.” he said.
Finally, when an effective vaccine becomes available, it must be produced in a safe, reliable, and reproducible manner following good manufacturing practices (GMP). “The process is expensive and not so simple. So, we must invest in resources to develop an effective process because once the trials are completed, the production process cannot be changed,” he cautioned.
He warned that if this process is rushed, there might be a situation where we are one step ahead but two steps back. “Development of an effective vaccine from scratch takes 15 years, but we are trying to do it in one or two because of COVID-19,” he stressed.
Premature Approval of Vaccines
When asked about the consequences of a premature vaccine approval influenced by non-scientific reasons, Dr. van den Bosch was quick to comment that politically motivated decisions are very dangerous. As an example, he refers to a relatively recent event when politics decided the rapid launch of an incompletely tested Dengue vaccine, and it proved to be a disaster.
“A Dengue vaccine was pushed by a country’s former ruling government in a bid to win an election. Unfortunately, the vaccine was blamed when people started becoming ill. It later turned into a political fight, and eventually, when the current leader assumed power, the vaccine was abandoned altogether. This not only prevented the protection of people against Dengue but also resulted in a loss of confidence in the regular children vaccination program, which is even more dangerous,” he added.
These mistakes have disastrous consequences, and several diseases are on the rise in such countries. For instance, measles vaccination has dropped below 70%, which is significantly lower than the herd immunity standard of 95%.
“Science should always lead, and I hope that regulatory agencies are careful because if something fails, then people will lose trust in vaccination. In addition, every single adverse event will then be attributed to the quality of the vaccine. Governments and health organizations must clearly communicate vaccine-related information to the public and make sure everyone is abiding by all the prescribed regulations.”
Dr. van den Bosch firmly believes that guidelines are in place to protect people from adverse events. So, when decisions are made, agencies must ensure there are no political interferences. So as long as politics stays out, he is happy with any revision in those guidelines. He is confident that things would sail smoothly if the scientists at work are left to their devices, and a transparent discussion is in place.
Besides politics, the other non-scientific factor that he is wary of is commerce. Companies must not regard money as a priority, and vaccines must not be for profit. Therefore, commercial interests should not influence decisions, and vaccine applications must solely be led by science.
Dr. van den Bosch ended the interview by saying that the US has always been a leader for the rest of the world, and it’s regrettable to note that Americans are not paying heed to expert advice. “Wearing a mask or taking precautions against a pandemic are not opinions, it’s science,” he concluded.
Interviewer & Editor: Rajaneesh K. Gopinath, Ph.D.
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