Vaccine Development Lessons From the COVID-19 Pandemic
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January 2020 saw a global health emergency announced by the World Health Organization (WHO), upgraded to a pandemic on March 11: COVID-19, a disease caused by the SARS-CoV-2 virus The WHO director general expressed concern at the spread and severity of the COVID-19 outbreak, but also at the levels of inaction.
Vaccine developers were lightning quick off the mark, with mRNA vaccines leading the way from early on. In late February 2020, Moderna shipped mRNA vaccines for SARS-CoV-2 to the National Institutes of Health (NIH) for a clinical study, and the first COVID-19 jab was administered to study participants in March 2020. An unprecedented push has delivered nine fully approved vaccines, and the WHO vaccine tracker lists 137 vaccines in clinical development.*
The experience has created a stack of lessons to assist in the development of future vaccines. Some of these lessons come from the successes, some from failures. They should help the world develop vaccines for some of the most difficult pathogens to vaccinate against and prepare for future pandemics – if the lessons are remembered.
Scientific advances occurring years before the pandemic proved crucial for COVID-19 vaccines. Researchers such as Professor Drew Weissman at the University of Pennsylvania, US, developed crucial technology licensed by Moderna and BioNTech-Pfizer for their mRNA vaccines in the decade before. This was also underpinned by research into lipid nanoparticles as the delivery vehicles. “This went back to work we did in the 1970s, where we showed that you could encapsulate and deliver things like nucleic acids,” notes Professor Robert Langer, chemical engineer at the Massachusetts Institute of Technology who helped found Moderna.
Research on successful mRNA delivery in animals was published in 1990, but instability of mRNA and inefficient delivery slowed advancement and discouraged investment in mRNA therapeutics, Weissman and colleagues noted in a January 2018 article. Steady advances, largely unheralded in media reports, allowed Weissman to tout “a new era in vaccinology” in this article, while outlining advances and positive results for flu, Zika virus and rabies virus in animals.
Thus, while mRNA vaccines surprised many, the research and development had been in motion for a long time. Already, in late 2017, Moderna had initiated an mRNA vaccine trial for cytomegalovirus in adults, which is now in Phase 3. Moderna’s pipeline now includes multiple COVID-19 vaccines, but also other respiratory viruses such as flu and respiratory syncytial virus (RSV). While the BioNTech mRNA pipeline targets cancers mainly, CureVac in Germany is aiming to develop mRNA vaccines for rabies, yellow fever, RSV and malaria.
In April 2020, volunteers at Oxford University received a jab of a vaccine candidate developed by Professor Sarah Gilbert and her team at the Jenner Institute. This vaccine, manufactured by AstraZeneca and approved for emergency supply in the UK in late December 2020, consists of a weakened version of a common cold virus from chimps modified to make the coronavirus spike protein inside of human cells. This was also a newly approved vaccine strategy, with the first adenoviral vector vaccine type receiving approval from the European Medicines Agency, a Johnson & Johnson Ebola vaccinein 2020.
Oxford also had a head start. Researchers had tried to induce a better T cell response to a flu vaccine by using a modified pox virus to express viral genes in 2014, and later reported on the chimp CdAdOx1 vector for vaccine candidates for Rift Valley fever in 2016, tuberculosis in 2018, Zika in 2018 and Middle East respiratory syndrome (MERS) coronavirus in 2017. Then, in December 2019, a trial with a CdAdOx1 MERS coronavirus vaccine began in healthy adult volunteers in Saudi Arabia. This allowed the Oxford group to start working on a vaccine for SARS-CoV-2 on January 10, 2020. Other viral vector vaccine candidates also moved rapidly toward clinical trials, with a J&J vaccine using a rare adenovirus subtype, Ad25, receiving conditional authorization in the US in early 2021. This vaccine was rooted in research by Professor Dan Barouch at Beth Israel Deaconess Medical Center, who worked and reported on a HIV-1 vaccine based on this adenoviral vector in 2018. Again, vaccine research funded for other diseases underpinned the development of the rapid development of the J&J vaccine.
There are a number of other vaccine types that were neither viral vector nor mRNA vaccines. Two Chinese firms, Sinopharm and Sinovac, delivered billions of doses of inactivated virus vaccines, with these two jabs making up nearly half of all doses. Yet another strategy was to develop protein subunit vaccines, exemplified by the Novavax vaccine, which the European Medicines Agency (EMA) recommended for conditional marketing authorization in December 2021. It also became the ninth vaccine listed by the WHO for emergency use. In fact, the traditional protein subunit approach to vaccines is being pursued by almost one-third of all COVID-19 vaccines in clinical trials, according to the WHO vaccine tracker.
While the winners of the COVID-19 vaccine race made headlines, at least 10 vaccine candidates that entered clinical trials were later abandoned, including those from Sanofi, CureVac and Merck, proving that success was not inevitable and it was sensible to pursue multiple vaccine strategies. “Typically, it takes a long time to make a vaccine,” says Dr. Angela Shen, vaccine policy expert at the Children’s Hospital of Philadelphia. “One of the lessons we learned is that we should support the different types of technologies, because you don’t know which one is going to cross the finish line.” The take-home message: rapid development of COVID-19 vaccines was based on years of research.
Money tap, regulatory flex
Funding will always be a limitation in the development of new medicines, but to advance a vaccine from basic research to market authorization requires firm financial commitments at each stage of the process. The injection of funding early in the pandemic, including under a public-private initiative (Operation Warp Speed) in the US that invested upwards of $18 bn in COVID-19 vaccines, incentivized and funded industry to move vaccine candidates forward. “We have three vaccines licensed in the US, but 26 are licensed globally,” notes Shen. “That’s remarkable and only happened because of really concerted investments, both deep and wide.” The non-profit Coalition for Epidemic Preparedness Innovations (CEPI) based in Norway also contributed funding to multiple COVID-19 vaccines.
Another lesson from the pandemic, says Professor Kingston Mills, immunologist at Trinity College Dublin, is “That the traditional timeframe for developing a vaccine of between five and ten years is out the window, with the rapid development of COVID-19 vaccines.” A second major lessons, he adds, “Is that mRNA vaccines work.” He notes that the newer vaccines were ready to go for other diseases, though regulatory agencies are always cautious about approving a new technology. Turning on the financial tap, in an emergency, allowed for expedited clinical trials and regulatory approval, notes Mills.
Indeed, another lesson, as Shen noted in a blog, is to utilize regulatory flexibility, with countries successfully “using emergency authorization mechanisms to facilitate the rapid availability of vaccines, without compromising the quality of regulatory review.” Such provisions grant market access to unapproved products to life-threatening conditions, where no adequate alternative exists. Regulators also worked closely with vaccine developers, with the EMA initiating rolling reviews and evaluating data on promising vaccines as they become available. Unusually, the US Food & Drug Administration (FDA) issued guidelines to manufactures in June 2020, outlining what it expected to see: vaccine candidates were required to meet an efficacy point of 50%. “They put down thresholds for things they typically don’t put a number on, needing to see at least 30,000 folks enrolled in a Phase III trial, as well as two months’ [of] safety data,” says Shen.
Great strides in vaccine knowledge had not translated into new vaccines because of conservative investment strategies and risk aversion to the enormous costs in developing vaccines, says Immunologist Professor Danny Altmann at Imperial College London. Moreover, vaccines were not seen as especially profitable, and were pursued primarily by a handful of firms, such as Merck, GSK and Sanofi. “Ten years ago, there were only three or four companies making vaccines on any great scale, and they saw this almost as a mission, a socially responsible exercise,” adds Mills. The pandemic has cast a spotlight on how vaccines can be a lucrative market, with calculations that Pfizer, BioNTech and Moderna are tapping $65,000 in profit every minute from COVID-19 vaccines.
Momentum, incentivizing development
The pandemic has transformed the vaccine landscape, injecting it with renewed optimism, and has accelerated acceptance of the nascent platforms of mRNA and adenoviral vector vaccines. “It is a bit like during the Second World War, starting with airplanes not far removed from the earliest biplanes, and then coming out of the war, we had jet planes and were almost ready for the space race,” says Altmann in London. “The pandemic provided an impressive impetus, partly because all the stuff was waiting in the wings, ready to go.” He notes renewed momentum to develop vaccines for roadblock diseases, such as Chikungunya, dengue, malaria, HIV and tuberculosis. One concern, he notes, is that the mRNA companies have been so successful and profit making, that we should not get sidetracked into thinking they are the only answer; even in terms of COVID-19. “We may well have other COVID vaccines up our sleeves in the future, and outside the urgency of this battle [with the omicron surge], that may do the job better and more durably,” says Altmann.
Here’s the big picture: COVID-19 shows that emerging infectious disease pose a real and growing threat to global health security, and the human and economic costs are vast, notes CEPI, and there are plenty of other viruses that could inflict another pandemic. CEPI was launched at Davos 2017 in the wake of the 2014/2015 Ebola outbreak in West Africa, which killed over 11,000 people and had an economic burden of more than $53 billion. It “showed us that very few vaccines are ready to be used against these threats,” CEPI states. Even though an Ebola vaccine had been under development for more than a decade, it “was not deployed until over a year into the epidemic”.
CEPI was formed to develop and deploy new vaccines to prevent future epidemics and allow access to these vaccines to those who need it. It has invested in 14 vaccine candidates, including a number for COVID-19, but also for Nipah virus, MERS, Chikungunya, Ebola, Marburg virus and Rift Valley fever. The COVID-19 experience demonstrates that there is a great need for such an intergovernmental plan to push forward the development of vaccines, which might otherwise languish due to lack of funding and a lack of incentive to develop a vaccine that may or may not be sold at large volumes. Collectively, these factors should all mean that we are better prepared for the next big infectious disease outbreak.
*As of January 2022.