Developing a COVID-19 Vaccine: the Facts that Matter

Innovation is our exit strategy for the COVID-19 pandemic—and plan A of that strategy is developing a vaccine. No other health technology has the same potential to return our lives to a semblance of what they were before the pandemic. But how close are we? Amid the barrage of news stories covering a range of more than 100 vaccine candidates in development, it can be hard to understand how close scientists actually are to delivering a safe and effective vaccine to the world. To help you sort through the disarray, our team at GHTC has answered some frequently asked questions to give you the facts that matter most.

• Why do we need a vaccine?

  Vaccines are one of the most powerful and cost-effective public health technologies available. They are the gold standard for prevention and will be essential for conquering the COVID-19 pandemic. Effective treatments and better diagnostics can reduce transmission and improve survival rates, but without a vaccine, our best preventive measure will remain social distancing, which has already taken an unprecedented toll on social services and the global economy. Until we have a vaccine, social distancing will likely need to be selectively loosened and tightened in response to transmission patterns of the virus, continuing its drag on local economies and increasing disparities. The burden will be especially heavy for low- and middle-income countries, where the cost of containment and mitigation may overwhelm resource-limited health systems, even as persistent health threats like HIV/AIDS, malaria, tuberculosis, and other diseases continue to demand action and resources. Our world will never be the same as it was before the emergence of COVID-19, but if we are ever to return near to where we once were, we will need safe and effective vaccines that allow local economies to restart with confidence.

• How are vaccines developed?

  Vaccines are some of the most complex health products to develop, and because of this complexity development is often slow and costly. A new vaccine typically goes through six stages of development: basic research and discovery, preclinical research, clinical research, regulatory evaluation, manufacturing, and quality control. Through this lengthy process, developers and regulators demonstrate that vaccines are safe and effective for mass distribution. During clinical research, a vaccine is first tested in phase 1 clinical trials in a few dozen people to evaluate safety, then in phase 2 on a few hundred people to evaluate safety and efficacy, and then in phase 3 on thousands of people to ensure it is fit for future distribution to millions. Between phases, researchers assess their findings and seek approval from regulators to continue to subsequent phases. After a vaccine is approved by regulators to be safe and effective, it must be safely produced in large quantities through complex and closely regulated manufacturing. To succeed at each stage of development, a vaccine developer must work through biological puzzles while taking on myriad risks of failure.

• How is it possible to develop a vaccine in 12 to 18 months?

  Vaccine development is typically a 10 to 15-year journey from discovery to market, traversing several stages of development that typically have little overlap. That may be surprising, but for developers, moving one stage at a time lowers financial risks, allowing them to pause after each stage and assess whether to continue investing in further research; for regulators, it allows them to evaluate findings to safeguard patient safety. The oft-cited timeline for developing a COVID-19 vaccine, however, has been 12 to 18 months—how will this be possible?

  

  To reach that ambitious goal, developers and regulators will have to move fast, shortening and stacking several stages of development to run in parallel. This unprecedented venture will require greater upfront funding, coordination, and higher financial risk than usually taken on by developers. But with some luck and significant support from government, it may be achievable. Here’s how:

  The two stages of vaccine development that take the longest are clinical trials (5–10 years) and commercial manufacturing (2–5 years). To produce a safe and effective vaccine in 12 to 18 months, developers and regulators will need to shorten each stage and advance them simultaneously.

  Clinical trials typically happen in three phases over 5 to 10 years so that vaccine candidates can be thoroughly tested for safety and efficacy. But for COVID-19 and other urgent health threats, clinical trials can be merged and adapted, which is why some COVID-19 vaccine trials are labelled “phase 1/2” Even with combined phases, developers and regulators will still need several months to confirm that a COVID-19 vaccine candidate is safe. Sufficient time is needed to find adverse reactions that are rare or delayed and to find less intuitive risks, such as immune enhancement, which worsens a person’s reaction to a disease. This was an early concern for developing a SARS vaccine. Researchers and regulators also need time to conclude how effective a vaccine is at preventing infection and how long that protection lasts. A constraint is that it would be unethical for researchers to vaccinate clinical trial volunteers and then intentionally expose them to the SARS-CoV-2 virus, so vaccine candidates must be tested on volunteers that might be naturally exposed. In other words, to run a clinical trial, researchers need to train health care workers to follow complicated clinical trial procedures and deliver vaccines to thousands of people during ongoing outbreaks—not an easy task.

  Safe manufacturing takes additional time. Vaccines are complex biological products delivered to millions of people, so their manufacturing processes must be carefully designed and scrupulously regulated. Most vaccines require purpose-built facilities, and construction typically takes several months to several years and does not begin until after successful clinical trials. But to produce a COVID-19 vaccine in 12 to 18 months, developers will need to begin constructing facilities and manufacturing a stockpile of doses while candidates are still being evaluated in clinical trials. This will require additional financing that can bear a higher risk of failure.

  Clearly, a 12 to 18-month timeline is dependent on many things going right, and it has its skeptics, some who believe it could take more than five years before a vaccine is widely available. But for now, it is our best hope.

• How have previous investments in global health benefited SARS-CoV-2 vaccine research?

  Developing a safe and effective SARS-CoV-2 vaccine on a dramatically compacted 12 to 18-month timeline is only conceivable because of past investments that we have made in global health research and development which have fueled new biotechnologies, manufacturing platforms, and clinical trial methods. In fact, nearly every advanced COVID-19 vaccine candidate in development is built on previous vaccine research for other global health threats, including Zika, Ebola, SARS, MERS, HIV/AIDS, malaria, tuberculosis (TB), and pandemic influenza:

  • Janssen’s candidate, funded by the Biomedical Advanced Research and Development Authority (BARDA), is based on a technology the company used to develop and manufacture its investigational Ebola vaccine and its Zika, RSV, and HIV vaccine candidates.
  • Moderna’s candidate, mRNA-1273, supported by BARDA and the National Institute of Allergy and Infectious Diseases, is built on a platform used to develop vaccines for other respiratory viruses including pandemic influenza.
  • The Jenner Institute, a nonprofit vaccine developer based at Oxford University, has a leading candidate based on technology that was developed for malaria vaccine research.
  • The Walter Reed Army Institute for Research is developing a protein vaccine based on previous research on vaccines for Ebola, Zika, and MERS.
  • Sanofi’s candidate is based on the company’s previous work on a SARS vaccine.
  • The Melbourne Children’s campus is evaluating whether the BCG vaccine, a century-old TB vaccine, might provide a temporary immune boost against SARS-CoV-2 in phase 3 clinical trials.

  
  

  In manufacturing, too, researchers are building on previous investments. One GHTC member, IAVI, is repurposing technology initially developed for an HIV vaccine candidate to produce an “end-to-end platform for flexible, low-cost production of epidemic preparedness vaccines,” including COVID-19.

  Previous global health emergencies, such as the West African Ebola epidemic, have left us with lessons about how to accelerate complex clinical trials and carefully and quickly regulate products amid the chaos of outbreaks. From these experiences, we have better insight on how to improve and accelerate research, development, and coordination to deliver needed products.

• Why should we invest in manufacturing now if we don’t yet have a vaccine that works?

  Vaccine manufacturing is an extremely difficult process. In contrast to drugs, which are mostly small-molecule chemical products, vaccines are complex, large-molecule biological products. This means that while drug production is a more controllable chemical process, vaccine production is a more variable process dependent on both the physical environment and thebiological fluctuations of the organisms used in production. The interaction between these variabilities is what causes most manufacturing failures and supply shortages in vaccine production and is what makes close regulation so important to producing safe, effective, and consistent vaccine products.

  Because of the complexity in manufacturing vaccines, most production facilities are purpose-built for specific vaccines and must be specifically approved by regulators—which makes it difficult and costly to repurpose those facilities. Because the startup cost of building a facility, sourcing raw materials, and hiring personnel for a single product is so high, a developer does not usually invest in building a new facility until it is confident that its vaccine will be successful. This creates delays in market entry ranging from several months to several years, depending on the complexity of the vaccine.

  With a global pandemic, however, we cannot wait several extra months—and certainly not several years—so we must proactively begin building and repurposing manufacturing facilities to produce stockpiles of vaccine candidates before we have full confidence in their success. Developers, however, may lack the resources or appetite to proactively build or repurpose manufacturing facilities for unproven products, so funders need to find ways to incentivize or co-fund facilities to lower the financial risk of building these facilities in advance. This means that funders will inevitably finance unsuccessful efforts, but it is the only way to significantly speed the development process.

  The Bill & Melinda Gates Foundation has taken steps in this direction with a commitment to support the construction of manufacturing facilities for several leading candidates with the expectation that only a few facilities might be used. But the Gates Foundation intends for its funding to be catalytic. With the projected global need far exceeding our current global manufacturing capacity, government investment is essential. The Biomedical Advanced Research and Development Authority has provided funding to scale the manufacturing capacity of at least three candidates (in partnership with Moderna, Sanofi, and Janssen); has provided funding over the last decade to increase the nation’s capacity to “fill and finish” vaccines; and has established a program for direct manufacturing capabilities—but it’s unclear whether these investments will be sufficient for addressing the COVID-19 pandemic in the United States, let alone the world. Governments need to keep proactively investing in facilities to ensure we are betting on enough candidates so that once a candidate is successful, we will have sufficient supply and capacity to serve the world.

  If we defer, and manufacturing begins only once a vaccine is approved, it will delay access and could lead to hoarding, choking supply to places with the greatest need. Adequate global manufacturing capacity will help prevent this troubling scenario and encourage equitable access.

• Which vaccine candidates are in clinical trials

  As of May 12, there were 12 vaccine candidates in clinical trials around the world:

  • Coronavac, developed by Sinovac Biotech Ltd, is in phase 1/2 trials.
  • Inactivated novel coronavirus (2019-nCoV) vaccine (Vero cells) and Inactivated Novel Coronavirus Pneumonia vaccine (Vero cells), developed by the China National Biotec Group, are both in phase 1/2 trials.
  • bacTRL-Spike, developed by Symvivo Corporation, is in phase 1 trials.
  • The BCG vaccine, the century-old tuberculosis vaccine, is being evaluated by the Melbourne Children’s Campus and the University Medical Center St. Radboud for protection against SARS-CoV-2 in phase 3 trials.
  • BNT162 mRNA vaccine, developed by BioNTech, Fosun Pharma, and Pfizer, is in phase 1/2 trials.
  • ChAdOx1 nCoV-19, developed by the Jenner Institute, a nonprofit drug developer based at the University of Oxford, with research support from the National Institute of Allergy and Infectious Diseases (NIAID), is in phase 1/2 trials.
  • INO-4800 DNA Vaccine, developed by Inovio Pharmaceuticals, Ology Bioservices, the International Vaccine Institute, and the Korea National Institute of Health, with funding support from the US Department of Defense and the Biomedical Advanced Research and Development Authority (BARDA), is in phase 1/2 trials.
  • LV-SARS-CoV-2-aAPC,developed by the Shenzhen Geno-Immune Medical Institute, is in phase 1/2 trials.
  • LV-SMENP-DC, developed by the Shenzhen Geno-Immune Medical Institute, is in phase 1/2 trials.
  • Recombinant Novel Coronavirus Vaccine, developed by the Tianjin CanSino Biotechnology and the Beijing Institute of Technology, is in phase 1/2 trials.
  • mRNA-1273, developed by Moderna Therapeutics with funding from NIAID, BARDA, and the Coalition for Epidemic Preparedness Innovations (CEPI), began phase 1 trials on March 16.

  
  

  For more up-to-date tracking of COVID-19 vaccines and other products, see these resources:

  • GHTC COVID-19 R&D Tracker (covers vaccines, therapeutics, and diagnostics supported by the US government)
  • Policy Cures Research (GHTC member; covers vaccines, therapeutics, and diagnostics being developed globally)
  • WHO DRAFT landscape of COVID-19 candidate vaccines – 20 April 2020
  • FasterCures, center of the Milken Institute (comprehensive coverage of vaccines and therapeutics)
• Why do we need so many vaccine candidates?

  According to Policy Cures Research, a GHTC member, there are more than 100 COVID-19 vaccine candidates in development around the world with 12 in clinical trials (as of May 12). Developing vaccines is challenging with rates of success lower than 10 percent. A robust pipeline makes it more likely that one or more candidates will be effective and match the product profiles we need.

  Pipeline variety is also important because different products may be needed for different settings. For example, it would be more difficult to deliver multi-dose, refrigerated vaccines in low- and middle-income countries because of limitations, such as leaner health infrastructure, fewer patient-system interactions, and limited cold chain storage and transportation. Fortunately, the current pipeline of candidates includes an array of technologies, some potentially more effective for different populations and settings than others.

  It is less likely this pandemic will be brought to heel with a single vaccine and more likely that several vaccines will be needed for different contexts. Policymakers must keep in mind that companies are more likely to invest in vaccines designed for high-resource settings over vaccines designed for low-resource settings. For effective mass vaccination campaigns, policymakers will need to find ways to encourage development of vaccines that can be delivered in low-resource settings.

• Why should the US government invest in vaccine research?

  For developers, creating a new vaccine is a high-risk investment that is costly and capacity consuming. In a pandemic this is doubly true, but robust government investments can de-risk private investments and accelerate product development timelines, allowing companies to take bigger gambles and shorten and stack several stages of research and manufacturing to speed development. Public investment in vaccines isn’t new—in fact, the US government has a long history of supporting vaccine candidates that have transformed public health.

  Investment from the US government has other benefits:

  • It gives policymakers leverage to ensure that vaccines are designed for a range of settings around the world, not just those with the strongest markets. Such candidates should be affordable; designed for low-resource health systems that might lack electricity or refrigeration; designed for ease of delivery; and available in sufficient supply for global needs. Many countries will be unable to respond alone, and if the virus remains out of control in one part of the world, it will continue to haunt the rest.
  • By lowering the entry costs for developers to compete, it encourages a robust pipeline of candidates which raises the odds of a successful vaccine.
  • It encourages collaboration and coordination among developers through partnerships and by eliminating downside risks to competition.
  • It can impel developers to include provisions that promote affordability and access.
• Why should the United States work with other countries?

  International cooperation is key for speeding vaccine development and can be a form of cost sharing with multiple countries coordinating resources and scientific expertise to advance promising candidates. The World Health Organization recently designed an unprecedentedly large international randomized controlled clinical trial called the Solidarity Vaccine Trial to simultaneously evaluate multiple vaccine candidates and produce quicker research results. The Coalition for Epidemic Preparedness Innovations (CEPI), a global partnership financed by other governments and philanthropic organizations, is also funding development of multiple candidates. Over the last few years, international collaboration fast-tracked development of the Ebola vaccine, which changed the course of the Ebola epidemic in the Democratic Republic of the Congo.

  After a vaccine is developed, international cooperation will be indispensable for ensuring every country gets access. Manufacturing and distribution will need to be global, requiring monumental logistics if all countries are to benefit.

• What should policymakers do?

  In addition to continuing to provide strong support for leading US government research and development agencies, including the Biomedical Advanced Research and Development Authority, the National Institutes of Health, and the Centers for Disease Control and Prevention—which have received significant funding through prior emergency supplemental bills—GHTC is recommending two additional investments that the US government should make to advance innovations, including vaccines, to combat COVID-19:

  • $200 million to the Coalition for Epidemic Preparedness Innovations (CEPI), to advance vaccine candidates for SARS-CoV-2. CEPI is advancing nine vaccine candidates and has put forward a $2 billion global ask to advance this portfolio. US support for CEPI will help ensure that vaccines developed will be deployed effectively and affordably worldwide.
  • $200 million for Global Health Programs at the US Agency for International Development (USAID) to advance and deliver innovations to help low- and middle-income countries prevent, prepare for, and respond to COVID-19 and other pandemic threats. USAID should be resourced to advance vaccine candidates and delivery systems well suited for delivery in very low-resource settings, in addition to other medical countermeasures such as diagnostics and therapeutics; medical devices and health technologies; personal protective equipment for frontline health workers and health facility innovations; and the financing, manufacturing, and delivery systems these essential resources require—all tailored to the unique constraints of very low-resource settings.

  
  

  In its multilateral policy, the United States should work with other global leaders to proactively invest in global manufacturing capacity and product delivery mechanisms. Increased commitments should be made to existing global health mechanisms like Gavi, the Vaccine Alliance, and the Global Fund to Fight AIDS, Tuberculosis and Malaria, which are positioned to play an instrumental role in helping low- and middle-income nations finance the purchase and administration of COVID-19 vaccines and treatments. Many countries will be unable to mount an appropriate response on their own, and if the virus remains out of control in one part of the world, it will continue to haunt the rest.