COVID-19: from treatment to prevention

by Apurva Govande

figures by Tal Scully

COVID-19, the disease caused by the newly discovered virus SARS-CoV-2, is a national emergency. We need a vaccine to prevent severe outcomes of disease, to successfully combat future outbreaks of this virus, and to ensure that businesses and schools can safely reopen. Until one is available, healthcare professionals can mitigate symptoms while deploying existing drugs that may show promise against COVID-19.

What is a vaccine?

Vaccines help prime and prompt a rapid response when the body encounters a virus, allowing for a faster recovery from disease. For example, an inactivated or attenuated (weakened) virus can be injected into the body to teach the immune system that it is dangerous. The immune system then prepares specialized cells that make defensive proteins called antibodies. Antibodies stay in the blood and provide immunity long after they are made. The specialized immune cells last even longer, providing lasting immunity (on the order of decades or lifetimes).If individuals encounter the virus they were vaccinated against, antibodies find and inactivate the virus, which reduces the time and severity of a sickness and can often prevent it entirely (Figure 1).

Figure 1. Vaccination: Vaccination reduces length and severe outcomes of disease by allowing the body and immune system to prepare in advance of being infected. Without vaccination, people would suffer from many more preventable diseases today. We need a vaccine for SARS-CoV-2 to prevent further outbreaks of disease.

The majority of vaccines are composed of attenuated viruses or isolated molecules, such as proteins on the viral surface, but vaccines can also be small protein fragments, engineered immune cells, and more recently, genetic material such as DNA or RNA. To generate the more traditional types of vaccines, laboratories mass produce proteins or research how to uniquely weaken each virus, requiring manpower and increasing the time to development and distribution. To shorten this time, vaccine researchers take advantage of an important biological concept, the central dogma. The central dogma of biology states that DNA provides instructions for making RNA, an intermediary molecule, which is then used to make protein, the workhorse molecules of all cells. The SARS-CoV-2 outbreak has prompted the rapid expansion of several technology platforms, including DNA and RNA vaccines never before clinically tested in humans. Rather than producing a viral protein in a lab, delivered DNA or RNA directs our cells to make parts of viral proteins that do not cause disease, and the immune system makes antibodies the same as it would had the protein been injected directly (Figure 2). Today, rapid production of DNA or RNA in large amounts only requires the sequence of the virus’s genetic material. The sequence of SARS-CoV-2 was identified and published by Chinese researchers on January 11th, 2020.

Figure 2. A variety of vaccines: Vaccines can be many different things, but all have the same goal: to prime the immune system to make antibodies that combat the incoming virus.

Earlier this year, the biotech company Moderna developed an RNA-based SARS-CoV-2 vaccine, while another company, Inovio, developed a DNA-based vaccine. Moderna and Inovio both received grants from the Coalition for Epidemic Preparedness Innovations (CEPI), an international organization promoting vaccine research and pandemic preparedness. For these novel vaccines, optimizing stability, delivery, and manufacturing scale without compromising quality and immune response will matter for eventual distribution. Both private foundations and government agencies are supporting these efforts due to the urgent need for a vaccine against SARS-CoV-2.

How is a vaccine developed?

Vaccine development moves through established pipelines that require rigorous safety and efficacy testing before public availability. After identification of a vaccine candidate, pre-clinical studies in cultured cells and animals ensure the vaccine elicits an effective immune response without being toxic, before clinical trials begin in humans. At this point, the FDA recognizes the vaccine as an Investigational New Drug (IND). The Phase 1 clinical trial assesses risk factors or adverse effects, what dose is required, whether this dose is the same for different individuals, and if the vaccine promotes healthy immune systems to make antibodies. The Phase 1 trial for the Moderna vaccine began in record time, just two months after the sequence of the virus was published, weighing the dangers of quickly developing human trials against the urgent need for a vaccine. Notably, RNA vaccines against other viruses have previously been tested in animals with limited adverse effects. Additionally, the length and types of immune responses tend to differ in animals and humans, highlighting the crucial need for human trials. The Inovio DNA vaccine established preclinical data before moving to Phase 1 trials.

If there are no risk factors or adverse effects in Phase 1 trials, Phase 2 and Phase 3 trials expand to more volunteers, increasing statistical power. Each phase has built-in objectives and endpoints and volunteers are monitored for months. After Phase 3, the vaccine must receive FDA approval before licensing and distribution. Then, Phase 4 is the last phase and includes ongoing studies of risk and side effects after the vaccine is distributed (Table 1).

Table 1. Clinical trial pipeline: A vaccine goes through several rounds of trials and evaluations before it is licensed to the public.

Once available, vaccine distribution follows guidelines recommended by the CDC and developed by the Advisory Committee on Immunization Practices (ACIP). In February, the ACIP met to discuss COVID-19 and SARS-CoV-2, and will meet again in June. Vaccine distribution areas include the 50 states, District of Columbia, and eight US territories and freely associated states. During the H1N1 pandemic in 2009, doses were distributed according to population in each distribution area. For example, a distribution area containing 10% of the population received 10% of the available doses of vaccine stock, shipped directly to hospitals, health clinics, and doctor’s offices designated by each area responsible for receiving and storing the stocks. Allocation within each area is based on state and local jurisdiction, and each is required to have a vaccine distribution plan in place. The CDC recommends vaccinating the highest-risk populations first. Moderna has cautiously stated that a vaccine could be available only to health professionals for limited use in the fall, and national vaccine distribution will likely follow practices from past pandemics.

What can we do before a vaccine is available?

Before a vaccine is widely available, compassionate use, Emergency Use Authorizations (EUAs) and the strategic national stockpile are designed to streamline responses during a crisis and mitigate the most severe cases. BARDA, a government agency, provides national funding for companies and programs dedicated to developing drugs and antivirals. The FDA issued EUAs authorizing use without trials and testing for healthcare professionals to test patients, use available ventilators and respirators, and for antiviral drugs. Several drugs and treatments developed in previous years have been used during this crisis.

Remdesivir, an antiviral drug that prevents the ability of a virus to make copies of its genetic material, was developed during the Ebola outbreak by Gilead and was authorized for compassionate use in SARS-CoV-2 infected patients. The FDA designates compassionate use for unlicensed experimental drugs in extreme cases. Since then, a Phase 3 trial showed some promise and Gilead has donated doses distributed nationally and internationally to help with the pandemic. The Institute for Clinical and Economic Review, a nonprofit organization, has released their recommendations for the pricing of Remdesivir.

 Additional EUAs for commercially developed antibodies and convalescent plasma (blood plasma from recovered individuals containing antibodies that combat the virus), may act as another stopgap measure before a vaccine is available. Convalescent plasma is transferred into patients who have severe disease to inactivate the virus. Like any blood donation, these transfers must be screened for diseases and compatibility. The use of convalescent plasma is not unique to this outbreak and was successfully used during the Ebola outbreak (Figure 3). Blood centers are working with the FDA to distribute donated convalescent plasma to hospitals.

Figure 3. Antibody transfer: Similar to a vaccine response, recovered individuals contain antibodies in their blood that we know effectively combat the virus. These can be transferred to ailing patients similar to a blood donation to try and reduce the most severe cases of disease. In some cases, it can also be protective. The antibodies act on the virus directly, preventing its ability to infect new cells.

How can we prepare for future outbreaks?

Social distancing, antiviral drugs, antibodies, and eventually a vaccine will help control the outbreak of SARS-CoV-2. While states have done their best, this crisis has exposed cracks in our healthcare system and preparedness. Questions remain that researchers are currently working to answer and require more time and data.

Will a vaccine promote lasting immunity? Follow-up studies will determine if volunteers have antibodies specific to SARS-CoV-2 in their blood months or years after vaccination. A second booster vaccine could be required if antibody levels drop below the limit of detection in blood. Some individuals that recovered from SARS-CoV-1, which broke out in the early 2000s, maintained immunity years after they had cleared infection. This could also be the case with SARS-CoV-2, and it remains to be seen whether recovered individuals and vaccinated individuals have lasting immunity. Will we be prepared for the next outbreak? We’ll need effective scientific and sociopolitical approaches to prepare and prevent future outbreaks. We continuously build off of previous research to improve response and preparedness, and this crisis is no different.

Apurva Govande is a fourth-year PhD student in the Program in Virology at Harvard.

Tal Scully is a second year Ph.D. student in the Systems, Synthetic, and Quantitative Biology program at Harvard University. You can find her on Twitter as @TalScully.

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