COVID-19, caused by the newly emerged virus SARS-CoV-2, first appeared in December 2019 in Wuhan, China. In the months since, the virus has infected more than 27 million people and caused at least 875,000 deaths around the world (at the date of this posting). The global pandemic has impacted many facets of daily life: remote work, virtual school, Zoom graduations and weddings, mask wearing, and not being able to go to movies, museums, sporting events, or eat in restaurants. And through it all, the persistent thought that we just need to wait for a vaccine and then everything can go back to “normal”. So, how do you make a vaccine to protect against COVID-19, and how long will it take?

Please note that this is an on-going and rapidly evolving situation. Data and research presented in this article represent the best available data at this point in time.

The race to make a vaccine began as soon as the genetic sequence of SARS-CoV-2 was published in January 2020. The scale of the pandemic has pushed researchers and regulators to move vaccine candidates forward at breakneck pace—while bringing a drug or vaccine to market generally takes a decade, many hope that a COVID-19 vaccine will be available by mid-2021, or sooner. This push is being helped along by government policies, such as the US government’s “Operation Warp Speed,” which aims to fund and coordinate vaccine development and manufacturing.

Before a vaccine (or drug) is made available, two fundamental questions—safety and efficacy—are addressed through clinical trials. How well a vaccine works, or its efficacy, is a measure of its ability to protect people against future infection with the particular pathogen, in other words, how much less likely is a vaccinated person to become infected following exposure to the virus compared to an unvaccinated person.

The first candidate vaccines for SARS-CoV-2 entered clinical testing in March, and as of September 2, there are 210 in development, with 30 of those at the clinical trials stage, according to data from the Milken Institute. Although most routine childhood vaccines are built on two standard approaches, or platforms, the majority of SARS-CoV-2 candidate vaccines represent a variety of more modern methods. For details of all the different candidate vaccines and updates on their progress through clinical trials, check: the New York Times and Milken Institute trackers.

The Moderna candidate

One of the most advanced vaccine candidates (as of this writing), is an RNA vaccine being developed by Moderna and researchers at the NIH. Their candidate, called mRNA-1273, consists of a lipid-wrapped piece of RNA encoding a slightly modified version of the SARS-CoV-2 spike protein, which is what the virus uses to enter cells. The body’s own cells will then use these instructions to manufacture the viral protein and show it to immune cells. This approach to making vaccines is largely unproven, but is expected to be easier and safer to make and use than traditional approaches, since there is no real pathogen involved. Interim results from the phase 1 clinical trial were published in July, the phase 2 clinical trial is on-going, and the start of a phase 3 clinical trial, aiming to enroll 30,000 participants, was announced in late July.

For the phase 1 trial, 45 healthy adults received 2 injections of mRNA-1273, 28 days apart. Three different doses were tested in the initial study, and the results prompted the selection of the 100μg dose to use in the phase 3 trial. The researchers noted there were no serious safety issues, although participants commonly reported mild to moderate reactions that increased with dose–including fatigue, injection site pain, and fever—which is not unusual for vaccines.

Next, researchers asked if participants’ immune systems were reacting to the vaccine candidate. They looked for two types of responses that might protect against future infection: antibodies that can “neutralize” or directly block SARS-CoV-2 from getting into new cells, and T cells that recognize pieces of the virus and can destroy infected cells or make cytokines to direct the action of other immune cells. Before receiving mRNA-1273, participants didn’t have these SARS-CoV-2 fighting antibodies. But within 15 days of the first injection, everyone had antibodies that recognized the SARS-CoV-2 spike protein—and about half of participants had antibodies with some ability to block the virus from invading new cells. Following the second injection, all trial participants had neutralizing antibody responses, which were similar or better than samples from COVID-19 patients, suggesting mRNA-1273 may be as successful as the virus itself at prompting this type of response. After both doses, participants had helper T cells that made antiviral cytokines in response to seeing pieces of the SARS-CoV-2 spike protein, but killer T cell responses were barely detectable.

Of note, this trial aimed to test the safety of this candidate vaccine, and its ability to provoke an adaptive immune response. Although participants will continue to be monitored for one year to track the durability of the observed antibody and T cell responses, we won’t know if mRNA-1273 protects against COVID-19 until results of the phase 3 trial are released. The on-going phase 2 trial is examining safety and immunogenicity in a larger, more diverse group of participants, including people over age 55.

The AstraZeneca candidate

Another promising vaccine candidate is a viral vector vaccine being developed by scientists at the University of Oxford and AstraZeneca. Viral vector vaccines are a precise, Mr. Potatohead-eque spin on traditional weakened vaccines. Scientists start with an unrelated, non-dangerous virus and swap out one or more pieces to make the vaccine look like the pathogen of interest. The “Oxford” candidate is made from a Chimpanzee Adenovirus (which doesn’t grow in people) that has been modified to carry the gene for the SARS-CoV-2 spike protein. They have started phase 3 clinical trials in Brazil, South Africa, and the UK, and published preliminary findings from a combined phase 1/2 trial in July.

For the study, which so far focuses on safety and immunogenicity, researchers recruited 1077 healthy adults in the UK who will continue to be monitored for the on-going efficacy portion of the trial. Participants were randomly assigned to receive the candidate vaccine or an unrelated vaccine (against meningitis-causing bacteria) as a control. Like its Moderna counterpart, this vaccine candidate had no serious safety issues, although mild to moderate reactions were again common (and reported more often than for the control vaccine).

All participants had antibodies recognizing the SARS-CoV-2 spike protein by two weeks after getting a single injection of the candidate vaccine, and their antibody levels remained elevated for at least 8 weeks (the latest time point for these interim results). Through in vitro experiments, the researchers found that all tested participants had made at least some neutralizing antibodies. Examining T cell responses, researchers found that most tested participants had immune cells that made interferon gamma, a type 1 cytokine important for antiviral responses, in reaction to pieces of the SARS-CoV-2 spike protein. This response peaked two weeks after injection of the candidate vaccine, but was still detectable for at least 8 weeks.

The trial also included a group of ten participants who received two doses of the candidate vaccine 28 days apart. The second injection didn’t raise additional safety concerns, but boosted overall antibody levels, improved results in the neutralizing antibody tests, and led to steady interferon gamma production in the T cell experiment.

These early results are a good sign, but they don’t say anything about the ability of this candidate vaccine to protect people against SARS-CoV-2 infection. Other caveats include: participants with pre-existing antibodies recognizing the SARS-CoV-2 Spike protein were not excluded from the trial, only a subset of participants were tested for antibody and T cell responses, and a lack of diversity amongst participants.

Other candidates…and other concerns

There are also several inactivated vaccine candidates being developed by Chinese companies that have entered phase 3 trials as of late July, but so far only Sinopharm have published their clinical results. Due to the low number of new cases in China, these companies have looked internationally for testing sites, with Sinopharm conducting their large phase 3 trial in the United Arab Emirates and Sinovac testing their candidate vaccine in Brazil. Although inactivated vaccines have a long track record of success against other diseases, there can be safety concerns around the growing and handling large amounts of virus that is infectious prior to its inactivation. Additionally, just as for the candidates discussed above, we await efficacy data from the phase 3 trials.

Despite the rapid advances and rosy press releases, many open questions remain. Will any of these vaccine candidates be effective in older adults, who are at higher risk from COVID-19, but whose immune systems often do not respond as well to vaccination? Can we glean anything from the early clinical trial data about how effective the first COVID-19 vaccines likely to be? Correlates of protection, which are measurable immune responses that are responsible for and statistically related to protection against the disease, are typically an important part of data collected during vaccine trials, but, crucially, we don’t yet know what they are for SARS-CoV-2. Most of the early clinical trial data has focused on total and neutralizing antibody amounts, with more limited results around T cell responses. But at this point scientists don’t know how many neutralizing antibodies are needed to protect against infection, or even if neutralizing antibodies alone (without a strong T cell response) are protective. However, once efficacy data from the first phase 3 trials is released, we will have a much better idea for what types of immune responses to look for in the next round of candidates. 

Another area of uncertainty is the rollout of a vaccine, once one is shown to be effective. Companies generally do not focus on manufacturing logistics until their drug or vaccine is approved, since doing so would be a waste of resources were the drug to fail. Although Operation Warp Speed is helping to fund earlier manufacturing, there is still concern about a lag between approval and mass production. So, how many doses will be ready when the first vaccine(s) is approved and how will those doses be distributed? Who gets the vaccine first (especially if early supplies are limited)? 

There is also the opposite quandary–will enough people be willing to get the vaccine? In a Pew research poll earlier this year, 27% of US adults said they would probably not get a COVID-19 vaccine . If that number has not improved when a vaccine becomes available, we may not be able to reach herd immunity, which is the level of population immunity needed to significantly slow the spread of an infectious disease.

With more than a dozen vaccine candidates in clinical trials, including several already progressing through to the final phase, it seems reasonable to expect some efficacy results by the end of 2020, and vaccine distribution to happen in 2021. The important thing is to remember that an effective vaccine will not immediately end the pandemic, though it will be a critical milestone. In the meantime, we should continue to practice social distancing and mask-wearing, work to improve science education and public health infrastructure, and fight against racial inequities and healthcare disparities. We’re in this for the long haul, and we’re in it together.

Featured image: “Study Participant Receives a Candidate Vaccine” by NIAID is licensed under CC BY 2.0