COVID-19 Vaccine R&D 101: The Facts That Matter
The arrival of the first wave of COVID-19 vaccines is bringing hope that 2021 could mark the beginning of the end of this devastating pandemic. While the rapid development of these first vaccines is an extraordinary scientific achievement, much work remains to ensure that people across the United States and world can access a vaccine—and achieving that will require continued investment in research and development (R&D) of COVID-19 vaccines.
To help you sort through the barrage of information and news on COVID-19 vaccines, GHTC answers frequently asked questions about COVID-19 vaccine R&D.
Last updated: April 2, 2021
Which vaccines are approved? And what is the status of ongoing development efforts?
The following vaccines have been approved for emergency use in the United States by the US Food and Drug Administration:
- Pfizer/BioNTech vaccine, approved December 11, 2020, for individuals ages 16 and up
- US government supported development through purchase commitment via funds from the Biomedical Advanced Research and Development Authority (BARDA) and the Department of Defense (DoD) as part of Operation Warp Speed (OWS).
- Moderna vaccine, approved December 18, 2020, for individuals ages 18 and up
- Was codeveloped by scientists at the US National Institute of Allergy and Infectious Diseases (NIAID) with additional financial support from BARDA as part of OWS.
- Johnson & Johnson vaccine, approved February 27, 2021, for individuals ages 18 and up
- NIAID and BARDA supported development as part of OWS.
Additionally, the following vaccines have been approved for emergency use by stringent regulatory authorities of other nations:
- AstraZeneca/University of Oxford vaccine, approved in the United Kingdom on December 30, 2020, for individuals ages 18 and up
- Gamaleya Research Institute Sputnik V vaccine, approved in Hungary on January 21, 2021
- Sinopharm/Beijing Institute vaccine, approved in Hungary on January 29, 2021
The following vaccines have either received full approval or emergency use approval from non-stringent regulatory authorities. Note: There is less public, verifiable data on these vaccines:
- Sinovac CoronaVac vaccine, approved in China and other nations
- Sinopharm/Wuhan Institute vaccine, approved in China and other nations
- Vector Institute EpiVacCorona vaccine, approved in Russia
- Bharat Biotech Covaxin vaccine, approved in India and other nations
- CanSino vaccine, approved in China and other nations
- Chumakov Center/Russian Academy of Sciences CoviVac vaccine, approved in Russia
- Anhui Zhifei Longcom/Chinese Academy of Medical Sciences vaccine, approved in China and other nations
Additionally, there are more than 80 vaccine candidates now in clinical trials in humans. Among those, the most advanced in phase 3 trials include:
- Novavax vaccine
- DoD and BARDA supported development as part of OWS.
- Curevac vaccine
- Clover Biopharmaceuticals/Dynavax vaccine
- Zydus Cadila vaccine
- AnGes/Takara Bio vaccine
- Institute of Medical Biology at the Chinese Academy of Medical Sciences vaccine
- Research Institute for Biological Safety Problems vaccine
- Abdala vaccine
- ReiThera/Lazzaro Spallanzani National Institute for Infectious Disease vaccine
- Finlay Vaccine Institute Soberana 2 vaccine
- Center for Genetic Engineer and Biotechnology of Cuba vaccine
- Pfizer/BioNTech vaccine, approved December 11, 2020, for individuals ages 16 and up
How effective are these vaccines in preventing illness?
Among those vaccines approved by stringent regulatory authorities, all have proved highly effective in preventing illness, particularly severe illness:
- The Pfizer/BioNTech vaccine was shown to be 95 percent effective in preventing COVID-19 illness in clinical trials.
- The Moderna vaccine was shown to be 94 percent effective in preventing COVID-19 illness in clinical trials.
- Russia's Sputnik V vaccine was shown to be 91.6 percent effective in preventing illness in clinical trials.
- The AstraZeneca/University of Oxford vaccine was shown to be 76 percent effective in preventing illness and 100 percent effective in preventing severe disease in a recent US-based clinical trial, while pooled results from trials in the United Kingdom, South Africa, and Brazil showed it at roughly 62 percent efficacy in preventing illness.
- Johnson & Johnson’s vaccine was found to be 66 percent effective overall in preventing moderate to severe illness, with an efficacy at 72 percent among participants in the United States. Overall, the vaccine was 85 percent effective in preventing severe illness.
- The Sinopharm/Beijing Institute vaccine has reported efficacy rates in preventing illness of 79 percent and 86 percent from different clinical trials.
Do the vaccines prevent vaccinated individuals from spreading the virus?
It is too early to know for certain for all vaccines. Efficacy results from the clinical trials measure how much a vaccine reduces the risk of an individual becoming symptomatic with COVID-19 illness. The trials were not able to measure whether the vaccines also prevent vaccinated individuals from transmitting the virus to others as asymptomatic spreaders, who harbor the virus but don’t themselves become sick. However, emerging real-world evidence on two of the vaccines suggests they do also reduce transmission. A recent study by the Centers for Disease Control and Prevention among individuals who received two doses of either the Pfizer/BioNTech or Moderna vaccine found that their risk of infection was reduced by 90 percent. Without infection, a person cannot spread the virus.
This is great news for broader efforts to end the pandemic. If new vaccines were shown to be merely “symptom reducing” rather than “transmission reducing,” then there would be a much tougher road ahead for controlling this pandemic.
However, if the vaccines are “transmission reducing,” then the concept of herd immunity comes into play. As more and more people become vaccinated, levels of transmission within communities will begin to decrease, which will mean it will become relatively safer for those still waiting to be vaccinated or not able to be vaccinated. At some point enough people will become vaccinated that herd immunity will be achieved—that is, enough of a given population will be immune to the disease to make person-to-person spread unlikely. The level of vaccine coverage required to achieve herd immunity is different depending on the nature of the disease and the efficacy of vaccines for it. Epidemiologists suggested a range of 70 to 90 percent could be required for COVID-19.
Are the vaccines safe?
Yes. While COVID-19 vaccines were developed and approved more quickly than has historically been the case for other vaccines, all vaccines approved by the US Food and Drug Administration and other stringent regulatory authorities have gone through a rigorous process of being tested via clinical trials in tens of thousands of volunteers to ensure they are safe and effective. These trial results were then reviewed and verified by independent scientists, who informed the approval decisions by these regulatory authorities.
During trials and subsequent vaccination efforts, some individuals have reported minor side effects from the vaccines, similar to those experienced when getting a flu shot, such as soreness at the site of injection, body aches, and fever. There have been a few reported cases of allergic reaction to the Pfizer/BioNTech and Moderna vaccines. However, these cases remain extremely rare, and health officials from the Centers for Disease Control and Prevention have stressed that the risk of illness or death from COVID-19 significantly outweighs the risk of serious allergic reaction after vaccination. While there have been some reports of rare blood clots among recipients of the AstraZeneca/University of Oxford vaccine, a causal link has not been proven, and the European Medicines Agency has emphasized the vaccine’s benefits outweigh risks.
How long will protection last?
It is too early to know. For some diseases, vaccines produce lifetime immunity, but for others, “booster” shots are required every few years to sustain protection. Based on knowledge of other similar viruses and the level of antibody response seen among vaccinated individuals, some scientists speculate that approved COVID-19 vaccines could offer at least a year to a few years of protection. However, at this point that is largely speculation. It is only through continued monitoring of vaccinated individuals over the coming years that we will learn the answer.
Will the vaccines work against new emerging variants or mutations of the virus?
Concerns have emerged as to whether vaccines approved and in late-stage development will be effective against new emerging variants of the virus, including those first identified in the United Kingdom (UK), South Africa, and Brazil. While studies remain ongoing, emerging evidence has provided a mixed picture, depending on the vaccine, variant, and study. Approved vaccines appear to be equally protective against the B.1.1.7 variant, first identified in the UK; however, studies have shown the vaccines either are or are likely to be less effective against the B.1.351 variant, first identified in South Africa, with results for the P.1 variant first identified in Brazil more mixed.
For the first-to-market mRNA vaccines, Pfizer/BioNTech and Moderna, lab studies have shown reduced antibody levels against the B.1.351 variant, suggesting some degree of diminished efficacy; however, Pfizer/BioNTech recently reported that its vaccine was equally protective among trial participants in South Africa, where the B.1.351 variant is dominant, though the number of South African participants was relatively small.
Among those vaccines that underwent large-scale clinical trials since these variants have become widespread, Johnson & Johnson reported phase 3 trial results that found that while its vaccine was 72 percent effective in preventing moderate and severe illness in the United States, in South Africa, efficacy was only 64 percent. Similarly, Novavax reported phase 3 trial results for its vaccine which showed it was 95.6 percent effective overall in preventing illness and 85.6 effective against the variant identified in the UK, while in a separate phase 2 trial in South Africa, efficacy was only 49.4 percent. Meanwhile, a small trial in South Africa found that the AstraZeneca/University of Oxford vaccine was not effective in protecting trial participants from mild to moderate illness caused by the variant prevalent in South Africa, leading the country to halt use of that vaccine, though research continues as to its efficacy in preventing severe illness, hospitalizations, and death.
While several vaccine makers have said that they could tweak their vaccine designs or introduce new booster shots to address new variants, and both Moderna and Pfizer/BioNTech are already initiating studies of such booster shots, the emergence of variants is worrisome and will certainly add complications and time to efforts to bring the pandemic under control.
How were scientists able to develop COVID-19 vaccines so quickly?
The first-to-market COVID-19 vaccines were approved for emergency use just 11 months after scientists first got their hands on the genetic sequence of the virus, an extraordinary achievement, especially given vaccine development has typically taken a decade or more.
A number of factors contributed to this success. First, while SARS-CoV-2 was a brand-new virus, scientists weren’t starting fully from scratch on vaccine development, since science builds on science. Previous vaccine research on similar viruses like Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), as well as other infectious diseases like HIV, malaria, Ebola, and influenza, helped researchers know where to begin and also advanced development of different types of vaccine approaches or platforms—which serve as a type of “template” for scientists to use in creating new vaccines. Two of the first approved vaccines, the Pfizer/BioNTech and Moderna vaccines, make use of a new platform approach called mRNA. (mRNA vaccines have been studied for decades, but this marks the first time vaccines using the approach have come to market.) Instead of using a weakened or inactivated form of a virus to trigger an immune response, mRNA vaccines give “instructions” to our cells to create a piece of the virus’s protein to elicit an immune response, and key here, because in this approach one can in essence “plug in” a new viral genetic sequence to create a new vaccine, mRNA vaccines are faster to design from the get-go to begin testing, which sped up the process to some degree.
Second, and most significant, developers were able to shorten and stack several stages of the product development process to run in parallel, including clinical trials, which typically take five to ten years, and commercial manufacturing, which often takes another two to five years. Vaccines normally go through three phases of clinical trials to test for safety, immune response, and efficacy in subsequently larger populations at each stage. In the case of COVID-19 vaccines, trials for safety and immune response (phases 1 and 2a) were often combined, as were trials for efficacy (phases 2b and 3), thus shaving off months between each trial phase, as you consider the time required for protocols to be prepared, approved, and for patients to be recruited. Additionally, product developers began manufacturing stock of their vaccines as soon as the vaccines were first developed, rather than waiting for this to begin after vaccines were shown to be effective and approved by regulators, as is normally the case. This was a huge financial risk (that governments and philanthropists financially backed, making it possible) that could have and still could result in unusable, ineffective vaccines, but it was key to significantly accelerating the speed at which vaccines reached patients. For example, this is why the first doses of the Pfizer/BioNTech and Moderna vaccines were able to hit the market within days of each being approved.
Third, regulatory agencies, like the US Food and Drug Administration (FDA), worked quickly to communicate with product developers about thresholds for approval and to review and approve trial protocols, applying lessons learned from vaccine trials during the West African Ebola crisis. The FDA and other regulators also used an expedited approval process designed for global health emergencies to approve vaccines for emergency use.
Finally, vaccine development efforts were facilitated by an unprecedented level of public-private sector collaboration and government funding. Normally, companies and their funders want to wait to see candidates successfully proceed through each subsequent stage of the product development process before putting in additional funding for the next stage, which can slow the process, but in this case significant up-front funding commitments for R&D and procurement allowed developers to plan for the end-to-end process from the start, thereby expediting the development process.
What are some of the top challenges in vaccine rollout?
One of the first significant challenges is manufacturing—producing enough vaccines to meet global need. Vaccine manufacturing is inherently a complex process. It involves creating biological products that must be produced with great consistency and protected from the introduction of outside contaminants to ensure product safety. That means manufacturers must routinely test batches and maintain careful safety protocols, with their facilities and processes reviewed and approved by regulators. Because of the complexity of vaccine manufacturing, most production facilities are purpose-built for specific vaccines, and there are startup costs and time involved in building facilities or retrofitting them for new vaccines. Additionally, every element of the final packaged vaccine, from the raw materials used in it, to the glass vials it’s stored in, to the dry ice it’s packaged in, presents opportunities for individual supply chain breakdowns and delays that ultimately can delay overall production timelines. While vaccine developers are working to increase manufacturing capacity, both by expanding and building their own facilities and partnering with generic or contract vaccine manufacturers to multiply production volume, producing enough vaccines to vaccinate the entire world will still take some time. Assuming two-dose vaccines, it will take the production of 12 to 15 billion vaccine doses to get about 80 percent of the global population immunized. With emerging variants raising the likelihood that vaccinated individuals may need to receive additional booster shots to remain protected, this challenge becomes even more pronounced.
The second set of challenges is around distribution and logistics. Simply put, it is hard to successfully get billions of doses to billions of people worldwide. Global and national guidelines must be translated to state and local action by a number of coordinated players, including government entities and private-sector health providers. As vaccines are shipped and stored for administration, they must be constantly kept at the right temperature to ensure they remain effective, which is commonly referred to as maintaining the cold chain. Among the first-to-market vaccines, the Moderna and Pfizer/BioNTech vaccines must be stored in pharmaceutical freezers that many facilities don’t have or can’t get or afford. This makes these vaccines logistically more difficult to distribute in smaller, rural health facilities that lack required infrastructure, whether that’s in a town in Iowa or a village in Sierra Leone. While the AstraZeneca/University of Oxford, Sputnik V, and Johnson & Johnson vaccines requires standard refrigeration that is much easier to maintain, even that can still pose a challenge for administration in some low-resource settings worldwide that lack reliable access to electricity. Another logistical challenge is ensuring patients receive the second dose of various two-dose vaccines at the right time to experience full protection, which will require significant follow-up on the part of health providers. It also requires double the syringes, storage capacity, and staff time. It’s not just the supply chain of actual vaccine doses that can create delays, but also supplies of syringes, personal protective equipment, and other tools health workers need for vaccine administration.
The third set of challenges is related to persuading the public to take a vaccine. In the United States, for example, nearly four in ten Americans reported they do not want to get a COVID-19 vaccine. Distrust is even greater among historically disadvantaged populations, including people of color. Vaccine hesitancy is not unique to the United States and will present an ongoing challenge in reaching high levels of vaccine coverage worldwide.
Finally, money is a challenge. This all carries costs. Within the United States, state and local health departments are struggling to shoulder these new costs. At the global level, many low- and middle-income countries can’t afford to obtain and distribute vaccines to their populations, creating a need for additional support from donor countries.
Given the challenges above, many experts believe that while significant portions of the population in the United States and high-income countries may have access to a vaccine by the end of 2021, billions of people worldwide may not receive access until 2022 or as late as 2024. There is also significant likelihood that COVID-19 will become another endemic disease, meaning that though cases will decline significantly in communities with high vaccination coverage, the disease will still continue to circulate to some degree and cause sporadic outbreaks among those unvaccinated.
Why should high-income countries like the US support efforts to ensure equitable access to COVID-19 vaccines globally as well as domestically?
Simply stated: 1) where a person lives should not determine whether they live or die; 2) no one is truly safe until everyone is safe; 3) COVID-19 could undo decades of progress in other health and development investments; and 4) it is a smart economic decision.
The circumstances of a person’s birth and where they live should not determine their right to health. It is the morally right thing to do to ensure everyone in the world can access a vaccine, whether they live in a small town in Nevada or a remote community in Nigeria.
It is also the smart thing to do. Even if high-income countries (HICs) achieve relatively high immunization coverage within their own borders, if the virus continues to significantly spread among unvaccinated populations worldwide, HICs will continue to see some level of reintroduction of the virus and small outbreaks among their own unvaccinated population. And given remaining uncertainty about how long vaccine protection lasts, reintroductions over the coming years could further complicate efforts to keep the virus in check domestically. Similarly, the slower the global scale-up of the vaccine is, the more likely we are to see the emergence of additional new variants of the virus. As discussed, these variants are already complicating vaccination efforts, thus rendering already vaccinated domestic populations at higher risk from COVID-19. No one is safe until everyone is safe.
If we do not support an adequate global response to COVID-19, we also risk undermining decades of investments in health and development programs. Already, the pandemic has set back global health progress by about 25 years. Routine immunization programs have dropped to levels last seen in the 1990s, and extreme poverty has increased by 7 percent. UNICEF estimates an addition 1.2 million children will die of preventable causes in just six months due to pandemic-related disruptions to health care, and The Global Fund to Fight AIDS, Tuberculosis and Malaria estimates an additional 1 million people could die of AIDS and tuberculosis in 2021. Through strong funding and decisive action to support vaccine scale-up worldwide, these trends can be reversed.
Supporting COVID-19 vaccination worldwide is also a sound economic decision. A recent analysis suggests that leaving low- and lower-middle-income countries (LLMICs) to fend for themselves in responding to COVID-19 will put decades of economic progress at risk for both LLMICs and advanced economies alike. According to the analysis, the cumulative economic benefit of an equitable vaccine solution accrued to ten top donor countries alone would be US$13 billion in 2020-2021 and $466 billion over the next five years, more than 12 times the estimated cost to do so. The United States has the most to gain economically for this effort, with $78.8 billion in potential benefits for 2021-2021 and $207.1 billion over the next five years.
The global mechanism that has been stood up to facilitate global vaccine research and access, which is modeled in the above economic analysis, is the Access to COVID-19 Tools Accelerator (ACT-A)’s COVAX Facility. COVAX was created to maximize the world’s chances of successfully developing COVID-19 vaccines and manufacturing and distributing them in the quantities needed to end this crisis. Through an advance market commitment and partnership involving more than 180 countries, COVAX is working to advance R&D and procure vaccines doses for participating countries, including doses for its 92 poorest countries, many of which have not been able to secure bilateral deals independently and are dependent on the facility for their population. COVAX is co-led by the World Health Organization; the Coalition for Epidemic Preparedness Innovations (CEPI), which leads the R&D side of its work; and Gavi, the Vaccine Alliance, which leads procurement and distribution efforts in partnership with UNICEF. The Biden-Harris administration announced in January 2021 that the United States is joining ACT-A and COVAX.
Why should we continue to invest in COVID-19 vaccine research now that we have vaccines that work?
There are a number of reasons to continue investing in COVID-19 vaccine R&D. First, more successful vaccines mean more available doses and production capacity. Manufacturing of vaccine stock is already underway for many of the candidates in late-stage clinical development. Thus, it is important to continue to support those efforts to fruition, because if they prove effective, the moment these vaccines are approved, more doses become immediately available and the world’s overall manufacturing capacity for vaccines is increased.
Second, to achieve aspirations to immunize the world, we will need second and third generation vaccines with characteristics that make them easier to deliver—like being single-dose and thermostable—as well as easier to manufacture in volume and more affordable. This will be especially important for reaching people in low-resource settings worldwide where barriers like lack of reliable cold chains and access to nearby health facilities can necessitate different types of tools. When vaccines are developed, the first ones to market are often less thermostable (meaning they must be kept at colder temperatures). That is the case with the Pfizer/BioNTech and Moderna vaccines, which must be kept at frozen temperatures. But over time, through continued research, developers often succeed in creating versions of a vaccine that can be stored at milder temperatures by adding new elements to the formulation. Further research can also lead to the creation of vaccines that are single-dose and thus easier to implement. Of the five first-to-market vaccines, only one—Johnson & Johnson—is single-dose. The other four—Pfizer/BioNTech, Moderna, AstraZeneca/University of Oxford, Sputnik V, and Sinopharm/Beijing Institute—all require two doses. Two-dose vaccines require double the volume to treat one patient, putting a strain on manufacturing capacity; are naturally more difficult to implement because of the need for careful patient follow-up; and are also more costly to health systems—two doses mean double the syringes, vials, storage capacity, personal protective equipment, and workforce labor required. Companies are also pursuing development of easier-to-administer formulations of COVID-19 vaccines, such as oral formulations, inhalable formulations, and versions administered by painless microneedle patches that stick on like a Band-Aid. Each of these innovations would make it easier to get vaccines to people in every corner of the globe.
Third, as discussed previously, there is still much unknown about how long vaccines will provide protection, their impact on reducing transmission, their effectiveness against emerging strains and to what degree existing vaccine regimens will need to be adapted against them, and more that requires continued study and investments in research.
If we have vaccines, do we still need to invest in R&D for drugs and diagnostics?
Yes. Based on current projections, it could take another two to four years to see significant portions of the global population vaccinated, and there is a high likelihood the virus will become endemic and continue to circulate at some level. There are also individuals, like certain immunocompromised people, that are unable to take vaccines. Thus, we will continue to need other solutions for COVID-19 including treatments, treatment as prevention approaches, and diagnostics, alongside continued use of public health practices like social distancing and masks.
While there are now a multitude of diagnostics on the market and many countries have made relative gains in increasing testing capacity, there is still a pressing need for more highly effective, low-cost, rapid point-of-care diagnostics that can be produced and deployed at mass scale. Similar to a home pregnancy tests, these types of tests provide a quick result, without a lab, and can be taken at home or at a health facility. While there are a few types of these tests now available, volume availability still remains low, and these antigen tests are often more likely to produce false negatives than traditional lab-based polymerase chain reaction tests, so further research to validate and improve these tools must continue. The emergence of new variants of COVID-19 is also complicating testing, as some existing tests are proving less effective in picking up these strains, underscoring the need for continued diagnostic research and validation.
In the therapeutic space, scientists have yet to discover a highly effective treatment option, underscoring the need for continued research. Only one treatment, remdesivir, has received full approval by the US Food and Drug Administration (FDA), but research suggests it may provide only a modest benefit to patients, and likewise evidence has been mixed for other antiviral treatments being studied. Research suggests repurposed steroids reduce deaths by about one-third among seriously ill patients by tamping down the immune system’s overreaction to the virus, but they are not recommended for individuals with mild disease. Two monoclonal antibody therapies, one from Eli Lilly and one from Regeneron, which have been approved by the FDA for emergency use, have shown promise in clinical trials in treating those in an early state of infection but have shown less promise in treating those with more severe illness. Monoclonal antibodies are a challenging category of therapeutics to scale up worldwide, as current options are expensive to manufacture and require intravenous infusion and a high volume of treatment. But product developers are pursuing research to produce monoclonal antibody therapies that can be delivered via a shot, just under the skin or into the muscle, and can be produced more easily and affordably, in the hopes of making this option more accessible worldwide.
What should US policymakers do?
GHTC is encouraging US policymakers to continue to provide additional supplementary funding, as needed, for US agencies now engaged in COVID-19 vaccine R&D and rollout, including the National Institutes for Health, Biomedical Advanced Research and Development Authority, Centers for Disease Control and Prevention, and Department of Defense. To specifically support the international side of the COVID-19 research response in the near and long term, GHTC is recommending:
- The US government join and contribute to the Coalition for Epidemic Preparedness Innovations (CEPI), a global collaborative effort to advance vaccines for emerging infectious diseases including COVID-19, via a US$200 million annual commitment. CEPI is supporting eight COVID-19 vaccine candidates in clinical development, four of which are not among Operation Warp Speed-supported candidates, so this complementary investment will increase the likelihood of bringing additional successful candidates to market.
- Congress provide $200 million in emergency funding for Global Health Programs at the US Agency for International Development to support the development of COVID-19 innovations designed for low-resource settings, including diagnostics.
- The US government leverage existing R&D efforts like Operation Warp Speed’s successor to continue to advance next-generation tools suited for the needs of low-resource settings and donate any excess vaccines globally once immediate US needs are met.
- The United States work alongside partner countries in the Global Health Security Agenda (GHSA) to revamp the GHSA Workforce Development & Medical Countermeasure Action Package to address gaps in R&D capacity.