The race for a vaccine against COVID-19 continues as the number of confirmed cases across the world continue to escalate. Vaccine development is known to be a rigorous process of testing together with strict regulatory rules over many years before commercialization. But what will it take to condense the usual trial period and yet preserving the necessary testing for safety and efficacy?
As the year 2020 draws to its final quarter, the world still continues to battle the ongoing COVID-19 pandemic, with a global death toll crossing the one million mark as of the beginning of October 2020. At the point of writing this article, there are 41 candidate vaccines in clinical evaluation and 151 candidate vaccines in preclinical evaluation. The pressure to create a COVID-19 vaccine in a short period of time is immense with the rising number to daily cases and many healthcare systems suffering from the overflow of patients. However, one would still have to consider what will it take to achieve such a feat in these times. Jerome H. Kim, M.D., Director General of the International Vaccine Institute (IVI) shared about COVID-19 vaccine development in a keynote speech at an online conference organised by Merck – A Paradigm Shift in Infectious Diseases: Lessons from a Pandemic.
COVID-19 is caused by SARS-CoV-2 that shares 79 percent sequence homology as the SARS-CoV virus that caused the outbreak of SARS in 2003. Dr Kim first begins his speech by addressing the question of whether the COVID-19 be like influenza or like rotavirus with regard to vaccines?
He highlighted that the mutation rate of SARS-CoV-2 is relatively slow compared to influenza virus and HIV-1 sequences found in the Democratic Republic of Congo
“From the vaccine development perspective, will COVID-19 be like influenza, where we require new vaccines every year, or will it be like a rotavirus where a single rotavirus vaccine developed in 2007 is still highly effective at preventing morbidity and mortality from rotavirus.” Said Dr Kim as he compared the mutation rate of the SARS-CoV-2 virus with the influenza and HIV-1 viruses.
Going on further, Dr Kim posed four key items to consider in developing a vaccine against COVID-19.
Four Key Questions in COVID-19 Vaccine Development
1. Does its infection provide immunity from further infection?
“Immunity to re-infection is a key component of human immune response and for those diseases for which vaccines have been successfully developed, that is normally the case. Which is the classic disease model that applies to for example, polio and Hepatitis A, meaning if you get the disease, you are immune from re-infection” Shared Dr Kim.
He then went on to contrast this disease model to disease for which no vaccines have been developed like the Human Immunodeficiency Virus (HIV) that is capable to causing death in the patient if not treated. Those infected are also unable to recover spontaneously and has the possibility of being super-infected again by a second strain of HIV.
“This demonstrates that the immune response to HIV is uncapable of controlling or eliminating HIV infection and subsequently unable to prevent reinfection. That may be one of reasons behind the difficulty in developing a HIV vaccine.” Said Dr Kim.
2. Which immune response is crucial for clearing SARS-CoV-2 infection?
“May be for the COVID-19 vaccine, we would need one that has a balanced immune response. One that triggers protective antibodies as well as cellular immune responses.” Said Dr Kim.
3. What is the appropriate animal model?
“If we have a good animal model it is much easier to develop a vaccine.”
“We do have studies on non-human primates that COVID-19 vaccines are able to protect monkeys against infection, what we lack now is the critical information from human studies. To show that the same COVID-19 vaccines that protect monkeys also protect humans against infection.” He explained.
4. Are there any safety issues?
“For vaccine development, safety issues are very critical to what we do. Which is a subject that goes back to the founding days of vaccinology.” Said Dr Kim.
Dr Kim shared how in the early days of vaccine development, the vaccine against cow pox was first thought to cause cows to appear on those who have been vaccinated. This same vaccine however, when on to eliminate small pox as a result of a safe and effective vaccine.
How Long will it Take to Develop a Vaccine?
Conventionally, it would take 5 to 10 years to make a vaccine, as it would have to undergo many stages of testing and regulatory approvals before being considered safe for human use and efficacious enough to prevent infection.
“It would normally cost a vaccine development company US$ 500 million to US$ 1.5 billion to develop a vaccine. This is associated with a failure rate, from the laboratory to licensure, of about 93 percent.” Dr Kim elucidated.
This means that only 1 in 10 vaccines actually make it all the way through the stage of testing and finally sold on the commercial market.
“With the cost and the failure rate of 93 percent, it isn’t surprising that major vaccine companies consider their target diseases very carefully.”
Phases of human clinical trials for vaccines:
Phase I: Conducted on 50 or fewer people to primarily look at the safety of the vaccine and to check if the vaccine will generate the correct protective immune response.
Phase II: Designed for the target population, such as the elderly or infants. Usually conducted for 100 or more individuals to test the immunogenicity and safety. Which means to test whether the vaccine develops the correct immune responses, like antibodies that might be released to neutralize the pathogen or cellular responses to kill infected cells.
Phase III: This phase involves thousands of volunteers, which can provide data that are crucial for licensure and commercialisation of the vaccine. It evaluates the safety and efficacy of the vaccine.
Accelerating Vaccine Development
Due to the urgent need for a vaccine against COVID-19, the same process would preferably be accelerated to achieve a viable and safe vaccine within six to 18 months.
Dr Kim shared how the phases of the entire clinical trial process will overlap to shorten the time period in an accelerated trial design. Preclinical and Phase I clinical trials would occur at the same time. After the final vaccination, usually at week 4 of phase I when safety of the vaccine is determined which is done by an independent safety and monitoring board looking at safety data specifically, enrolment of phase II will ensue. Subsequently, four weeks after the final dose of phase II is administered, safety and immunogenicity are evaluated. Once the vaccine is considered safe and induces the correct protective immune response in the target population, the vaccine then moves on to phase III.
“Some companies have been skipping the immunogenicity stage and moving directly from phase II to phase III, looking simply at safety. Being relatively sure of their vaccines as many of these vaccine platforms have been tested in humans before. Making them confident that their vaccine will make the correct immune response.” Said Dr Kim.
Moving on to phase III, Dr Kim highlighted that it could be designed with an endpoint, so that when a certain number of infections occurs, the first analysis of efficacy and safety can be done. If the results are promising, it would be theoretically possible that in 12 months or so we might know whether the vaccine is safe and efficacious.
In the conventional timeline of vaccine clinical trials, safety information on the vaccine is collected from the start of the trials to the end at phase III. Safety information is also still being collected while the vaccine is being prepared for regulatory approval, translating to 5 to 10 years of safety data available depending on how long it took to develop the vaccine. By comparison, in the accelerated vaccine clinical trial schedule, safety data might not be sufficient due to the short amount of time.
“So, when we commit to the accelerated design and execution of clinical trials for efficacy and safety, we really do need longer periods of follow-up for volunteers who participated in phase I, II, and III trials to ensure that the vaccine over the longer term is safe. Which will be very important information for consumers in order to prevent COVID-19 infections in their communities.” Said Dr Kim.
How to Convince Companies it is Worthwhile?
Dr Kim highlighted how the U.S government invested US$ 8 billion to a number of pharmaceutical companies as well as the Coalition for Epidemic Preparedness Innovations (CEPI) pumping in US$ 1.4 billion for COVID-19 vaccine development in order to mitigate risk and accelerate the process.
“What the U.S government is doing is leveraging its own funding against the risk that the vaccine development companies are taking. This is to encourage companies to move ahead with accelerated vaccine testing not knowing if it will work. But they are assured by the commitment of governments and organizations funding because of the urgency of the COVID-19 crisis.” Said Dr Kim.
Since the discovery of the COVID-19 disease in the city of Wuhan, Hubei province in China, identification of a vaccine candidate against this novel coronavirus has accelerated at an unprecedented speed. Within a short period of time, many companies and research institutions have started working on developing a safe and effective vaccine against COVID-19.
Published clinical data on the immunogenicity and safety of various candidate vaccines have shown promising results against COVID-19. Due to the high speed at which companies are releasing data on their clinical trials, Dr Kim alerted how the publication of positive COVID-19 vaccine results in press releases and not first through an article or a scientific journal that has been peer-reviewed could pose gaps in understanding the specifics of the potential COVID-19 vaccine.
Ensuring Affordability and Global Availability
The COVID-19 pandemic has affected many countries across the world, as the vaccine is still currently being developed, some organisations have joined forces to ensure that the vaccine when available will be benefit as many people globally as possible.
CEPI, WHO (World Health Organisation) and Gavi, The Vaccine Alliance, each have individual responsibilities in ensuring equitable access to the COVID-19 vaccine through COVAX. Over 150 countries have joined COVAX, for global access, coordinated strategy for vaccination, and ensure solidarity and collective ownership for the COVID-19 vaccine. COVAX will support low to middle income countries to ensure about 20 percent of required vaccines are provided.
“I really like to know how COVAX will end up, because if we can move forward with COVAX, then we can be relatively assured that by the end of 2021 that there will be two billion doses of vaccine available for countries around the world through the COVAX mechanism.” Said Dr Kim.
- World Health Organization, Landscape of COVID-19 candidate vaccines. (September 30, 2020). Retrieved from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
- World Health Organization, COVAX: Working for global equitable access to COVID-19 vaccines. (n.d.). Retrieved from: https://www.who.int/initiatives/act-accelerator/covax