Bence Kover explains what made the rapid development of Covid-19 vaccines possible and comments on their efficacy and safety.
The coronavirus pandemic brought a quantum leap in vaccinology, as next-generation vaccines were produced in record time. The vaccines that were optimistically promised to come in 18 months were delivered in less than a year. The previous record was held by the Mumps vaccine, licensed in 1967, which was developed in four years. This breakthrough is not without questions though. How effective are the vaccines? Are there valid safety concerns? What does this mean for the future?
While the rapid development of coronavirus vaccines might seem enigmatic for most, it is a result of a combination of previous research, enormous public and private funding, and a great deal of luck. Soon after the genetic sequence of the disease causing SARS-CoV-2 was released in January, vaccine developments started. Luckily some companies were already working on vaccines that were quite easy to adapt to this new pathogen (Moderna had several mRNA vaccine candidates, Oxford’s vaccine for MERS was already being developed). Besides the fact that coronaviruses were well studied and we had some experience of SARS and MERS already, scientists were also lucky that the mutation rate of the virus was relatively slow (unlike influenza) and it does not evade the immune system that easily (like herpes).
People commonly think that vaccines are developed for years because firstly they are so hard to make, and secondly their safety has to be monitored over a long period of time. Not to belittle the scientific effort behind the vaccines, but it was never the science that held back vaccine development, and we will see how this time vaccines were actually ready in a few weeks. Also, vaccines have never been monitored for longer or more closely than they currently are.
Figure 1. Timeline of the development of the Pfizer-BioNtech vaccine
The truth is that vaccine development is not different from anything on Earth in terms of the fact that it is controlled by financial interests. Securing funding for the lengthy clinical trials and getting through the bureaucracy of regulatory agencies is what usually takes years or decades. Vaccine development can require up to a billion dollars in expenses with no guarantee of success.
Vaccines (and pharmaceuticals as well) have to go through various stages of clinical trials. Generally, vaccine research starts with the pre-clinical stage where a vaccine is tested for efficacy, toxicity and pharmacokinetic details. At this stage, researchers commonly use model organisms (organisms commonly used in research with well-studied genetics) or immortalized human cell lines, but no actual human subjects participate. Phase I clinical trials usually involve 50-100 volunteers, who would be tested to find out the ideal safe dosage. In Phase II clinical trials efficacy and potential side-effects are assessed amongst a few hundred individuals. In some cases, Phase I/II trials are done to speed up the process, as it was the case for the current vaccines. In Phase III a larger sample size of 500-3000 people is recruited to assess the efficacy of the vaccine on a population level, comparing it to other alternative treatments.
Efficacy looks at the extent to which fewer infections occur in the vaccinated experimental group compared to the control (placebo) group. In the case of a vaccine that is said to have a 95% efficacy, for every 100 infections in the control group there are only 5 (100-95) infections in the vaccinated group. For diseases with high population prevalence, smaller sample sizes will obviously work, but for SARS-CoV-2, which has only infected a minor percentage of the population, larger sample sizes were required (which has obvious benefits as we will see).
After phase III, vaccines are ready for commercialization, but are still closely monitored as part of the Phase IV, which is also called post-marketing surveillance.
To pass from one stage to the next, large amounts of funding is required, and the paperwork can take months or years. The enormous public and private funding going into finding a coronavirus vaccine is unrivalled in history. In 2020, companies could enter the vaccine race with nothing to lose, as their financial risks were largely covered by public sources or philanthropic efforts. The lack of financial risk also fuelled an immense discussion between academics and corporations via open databases and pre-print servers, showing how cooperative people can be when not having to compete with each other for funding or profit.
Furthermore, with respect to the emergency situation, vaccine candidates were going through clinical trial phases simultaneously which significantly reduced the time required. Also paperwork and communication of results was done on a rolling basis, without the need to wait for the end of each trial and take months to write a dossier of material required by bureaucrats. Finally, in 2020 emergency-use authorizations were often given by key regulatory agencies in the EU and the US, to speed up the process. Still, even with all this help, from the hundreds of vaccine candidates (321 in September 2020) only a few managed to make it through the regulatory and production bottleneck.
How do the vaccines work?
Vaccines work by presenting a part of a virus called the antigen to the immune system, which triggers an immune-response resulting in long-term resistance to the pathogen (immunity) afterwards. Classic vaccines used killed or weakened (“attenuated”) viruses, which had no pathogenicity, but were still effective enough to cause immunity for the real pathogen. For SARS-CoV-2 this is how the two Chinese vaccines by Sinopharm and SinoVac work.
The vaccine made by the university of Oxford and AstraZeneca presents a step up from the classic methods, as it makes use of recombinant DNA technology. In this case, the DNA (the blueprint) of SARS-CoV-2 spike protein (the antigen) is engineered into a chimpanzee virus that carries it into human cells. After human cells produce the antigen from its blueprint, the immune system can respond, and the individual becomes immune for the actual SARS-CoV-2 (without ever being exposed to one). A very similar method is used by the Russian Sputnik, the American Johnson & Johnson and the Chinese CanSino vaccine as well.
Figure 2. Comparison of some of the approved vaccines
Finally, there are the next-generation vaccines made by Moderna and Pfizer/BioNtech, that build on the completely new technology of mRNA. Here, the blueprint of the antigen (SARS-CoV-2 spike protein) is in the form of mRNA (literally “messenger” RNA) that is a transient information carrying molecule using the same language DNA is written in. This mRNA is packaged into a lipid (oil) particle, which allows efficient delivery to cells. This method is revolutionary, because it allows rapid development and simple manufacturing of vaccines for any virus once its genetic sequence is known. It is not a surprise that BioNtech said they could produce a new vaccine in 6 weeks if COVID mutations require that. The only downside to these vaccines is their difficult logistics as they need to be stored at -70 °C (Pfizer) or -20 °C (Moderna).
(There is also a fourth category of vaccines that deliver the antigen (SARS-CoV-2 spike) in its protein form some way or another. There is a vaccine based on this idea made by the American Novavax which recently showed 89% efficacy in Phase III trials in the UK, and Boris Johnson has already announced the UK will secure 60 million doses of this vaccine.)
How effective and safe are they?
The debut of next-generation vaccines was impressive to say the least, as both the Pfizer and Moderna vaccines have around 95% efficacy. Furthermore, it has been observed that these vaccinations provide orders of magnitude better immunization than natural infections.
To stop the pandemic the R0 (number of people infected by an infectious individual) of the virus has to be brought down to 1 or less. As the R0 of SARS-CoV-2 is about 2-3 without lockdowns and social distancing, 60% (1-1/2.5) of the population has to be immune to the virus to stop the pandemic. So vaccines need to be at least 60% effective. However, efficacy is defined based on disease prevalence, and herd immunity depends on virus transmission. Therefore, it is not entirely clear what percentage of the population needs to be vaccinated to stop the pandemic. Simply put, some people might still be able to asymptomatically spread the disease even though they are vaccinated. This efficacy factor will be considered in the coming months of follow-up studies and policy planning. Our best bet is to vaccinate the whole population as fast as possible, targeting the most susceptible groups such as healthcare workers and the elderly first.
Previously, I mentioned that phase III clinical trials commonly include 1000-3000 individuals. However, in the case of the current vaccines this number was in the range of 30-40 thousand (Table 1.). This large sample size allowed scientists to examine the safety of each vaccine with a very high statistical certainty. The next-generation vaccines had similar reactogenicity (side-effects) to common vaccines that are already in use. Participants of each clinical trial have been and still are closely monitored.
Currently, there have already been 100 million doses of vaccinations administered world-wide and no pattern of harmful side-effects has been observed. The availability of multiple vaccines is a blessing as some vaccines might be more effective to certain groups of people than others. Furthermore, worldwide manufacturing and distribution is easier for multiple different vaccines as they all use existing facilities and technologies to a different degree. Lastly, having more vaccines allows for better logistics, and avoids overdependence on certain supply chains.
The only way out of this pandemic is vaccination, and hopefully everything will return to normal by the second half of 2021 . However, that “normal” might still look slightly unusual as it will contain vaccination-passports, and certain habits such as mask wearing might stick around. Either way, the past year showed what human collaboration can achieve when appropriate funding and flow of information is available, which makes me very excited for what the coming decade holds!
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