For this update, I’d like to discuss the pending vaccination for COVID-19. Since January, when the genome for SARS-CoV-2 (Severe Acute Respiratory Syndrome coronoavirus 2–the strain of coronavirus that causes COVID-19) was released, there has been work by researchers to develop a vaccination that produces an immune response in humans that allows our bodies to fight the virus.
Phases of making a Vaccine:
- Preclinical Testing: Researchers give the vaccine to animals to see if it produces an immune response.
- Phase I Safety Trials: Researchers give the vaccine to a small number of people to test the safety and dosage of the vaccine as well as the immune response. (Dr. Fauci mentioned in a recent interview that this number is as low as 45 in one of the trials, typical numbers are between 40-80 participants.)
- Phase II Expanded Trials: Researchers give the vaccine to hundreds of people split into groups, such as children and the elderly to see if the vaccine acts differently in them. Researches will first test adults, and then gradually step down the age of subjects if the vaccine is intended for children. Further safety tests and ability to stimulate an immune response will also be monitored.
- Phase III Efficacy Trials: Researches give the vaccine to thousands of people (30,000 people in 89 different locations in the US in the current Moderna and NIH trial) and wait to see how many become infected, compared with volunteers who received the placebo. The vaccine would have to protect at least 50% of vaccinated people to be considered effective for the current pandemic. Phase III trials are randomized and double blind. This is considered the gold standard of research. In a double blind study, neither the researchers or participants will know who is receiving the vaccine or the saline solution (placebo).
- Approval: The FDA and regulators in other countries will review the trial and decide on whether to approve the vaccine or not. The vaccine could receive an Emergency Use Authorization (EUAs are used to get products to the market before a formal approval is issued. In situations such as a pandemic this would help alleviate some of the regulatory burden to speed up the process.) Once the FDA approves a Biologics License Application for a vaccine, the FDA will inspect the factory where the vaccine will be made and approve the labeling of the vaccine. The CDC and the FDA will also continue to monitor the vaccine through the Vaccine Adverse Event Reporting System (VAERS) which monitors and detects new, unusual, or rare adverse events, identifies potential patient risk factors for particular types of events, and assesses the safety of newly licensed vaccines. There is also a Rapid Cycle Analysis program that was launched in 2005 that monitors real time data of adverse events in recently vaccinated people.
- Combined Phases: Some coronavirus vaccines in development are in combined Phase I/II trials (first testing on hundreds of people instead of a small number to accelerate the process). There are also some combined Phase II/III trials.
Vaccines currently in Phase III or combined Phase II/III trials are:
- Moderna in partnership with the NIH (National Institutes of Health) **Government support is nearly $1 billion
- German company BioNTech in collaboration with Pfizer, an American pharmaceutical company and Fosun Pharma, a Chinese drug maker **Government contract awarded with $1.9 billion with the option to extend, their trial will have 30,000 participants at 120 sites globally
- British-Swedish pharmaceutical company AstraZeneca in collaboration with the University of Oxford **$1.2 billion support from the US
- Chinese company Sinopharm **trials are launched in the United Arab Emirates and this company is state-owned (business enterprise where the government or state has significant control)
- Privately owned Chinese company Sinovac Biotech launched a Phase III trial in Brazil and is building a facility to increase manufacturing capabilities
- Australian based Murdoch Children’s Research Institute has a Phase III trial underway
According to the CDC, after a new vaccine has gone through Phase III and tested for efficacy (does it work?) and safety (does it cause harm due to side effects or health concerns?), many vaccines undergo Phase IV. Phase IV involves formal, ongoing studies after the vaccine is approved by regulatory agencies such as the FDA and a division called Center for Biologics Evaluation and Research. A committee of the World Health Organization (WHO) makes recommendations for vaccines used internationally and many countries have adopted the WHO’s standards.
So you can see that vaccines are developed, tested, and highly regulated because the number of human subjects in vaccine clinical trials is usually high and post-licensure monitoring of vaccines is closely examined by the CDC and FDA.
Some questions I’m getting about the vaccine trials for COVID-19:
- When will a vaccine be available? Operation Warp Speed is our Federal Government’s effort to make a vaccine available as soon as one can be determined to be safe and effective. Currently, the federal government is funding $10 billion towards eight vaccines that are in Phase III or will be starting Phase III by the end of September, according to Dr. Moncef Slaoui, chief advisor of Operation Warp Speed. (See above for current Phase III trials and amount of funding). Dr. Slaoui has an optimistic prediction that a vaccine will be available to all Americans by the end of 2021. We’ve been able to get to the Phase III trials in record speed because of newer technology as well as the ability of the coronavirus to illicit an immune response, according to Dr. Fauci. There is new and interesting research showing that some people are capable of producing a T-cell response (type of immune response) to COVID-19 just by being exposed to other types of coronavirus strains of which there are many. More on when a vaccine may become available at the summary of this post.
- Who will get priority when the vaccine becomes available? There is a committee to determine just this called the Advisory Committee on Immunization Practices. The committee, along with ethicists and vaccine experts who have been asked to weigh in as well, has the difficult task of determining if high-risk individuals which include the elderly and people with health conditions such as elevated blood pressure, diabetes, and heart disease will be injected first. Or, perhaps, the volunteers that participated in the studies that got placebo should be compensated for their efforts by getting first pass at a new vaccine? Much of this decision making will depend on the information we get from the research trials. We need to know if the elderly or high risk individuals will be able to produce an effective immune response. We will need to see if there is a particular population that will be prone to adverse events of a vaccination. The committee will be tasked to weigh the many risks verses benefits of a new vaccination based on as much scientific information as possible before making these decisions.
- Will there be enough doses of the vaccine for everyone when it does become available? The Federal Government along with the NIH is contracting with different manufacturing agencies by reserving capacity at existing centers like the Texas A&M Center for Innovation in Advanced Development and Manufacturing as well as working with organizations like North Carolina’s Fujifilm Diosynth Biotechnologies Center to ramp up a production of a vaccine candidate being developed by Novavax. Novovax is hoping to have its vaccine candidate available for Phase III clinical trials by September. The United Parcel Services, Inc. (UPS) is building two giant freezer farms capable of super-cooling millions of vials of COVID-19 vaccine, preparing for the day it may need to deliver it at high speed both in the US and globally.
- How effective will the vaccine be? The FDA has said that it would accept 50% efficacy rate. For comparison, most of our vaccinations currently have an efficacy rate of upper 90s like the measles vaccine at 97-98% efficacy. Some are between 80-90% efficacy rate such as tetanus and pertussis. The flu shot is 40-60% effective. This is why the flu vaccine is tweaked yearly and given so often. We still recommend getting the flu shot despite a lower efficacy rate because it reduces the severity of flu and reduces intensive care admissions and deaths.
- How many times will we need to be vaccinated for the shot to be effective? This is unknown at this time. The vaccine may require booster shots every year or so. It will depend on the current trials and post-vaccination studies.
- How does the proposed vaccine work? There are many different ways for the vaccines to work that would require another long blog post to review. The genome of the SARS-CoV-2 virus, the virus that causes COVID-19, was deciphered from a sample of a 41 year old man who worked a the seafood market in Wuhan where the first cluster of cases appeared. From this genome, researches have identified genes for proteins that carry out a range of jobs for the virus, such as making copies of the virus or interrupting affected cell’s production of their own protective proteins. The vaccine trials are working on different areas of the COVID-19 virus to prevent it’s effects on human cells.
The rate of getting a vaccine will depend on running the numbers between the 2 groups of participants in the vaccine trials. We need high enough number differences between vaccinated people who become infected/sick verses the people who got a placebo who become infected/sick with COVID-19. The higher the number of those who get the placebo (no vaccine) and get sick verses the (much lower) number of those who get the vaccine and become infected/sick will yield a statistically more valid result. A study will conclude early if it becomes apparent that a vaccine will cause a more favorable outcome, such that not vaccinating people would be unethical.
There are a few ways that we can get a quicker vaccine. If we are able to place the trials in hotspots where outbreaks are occurring in a smaller geographic area, then we’ll have better chances of getting higher numbers of people infected. Some trials are targeting essential workers like grocery employees and health care workers that are higher for risk of infection. Some trials are just trying to get a large number of participants.
Because we need enough data to make decisions on approvals for certain vaccinations, we need to be careful not to rush the process to get accurate results. It looks like we are doing trials in areas of high risk of infection such as the US and Brazil. We are funding the trials and subsequent manufacturing of vaccinations if one becomes available. What remains to be seen is if the FDA, CDC, and other regulatory agencies as WHO will maintain strict criteria for good evidence before approving a vaccine. We also would hope that the process will be a transparent one so that the public on a global scale will feel confident in getting the vaccination. Since the process of going from Phase III trials to approval can take a year to many years, we should be leery of a company or country that claims to have an effective vaccine in several weeks, such as the Russian Gamaleya vaccination with the possible September production date.
There is also the real possibility that none of these trials will yield an effective vaccination. In this case, we would still need to rely on measures that have proven to be effective such as hand washing, wearing a mask, and social distancing–however difficult these measures are. And continue taking care of yourselves, get some exercise, sleep, healthy diet, social media and news breaks, reach out to friends and your community. Try to have patience as this too will pass eventually. As Ralph Waldo Emerson put it, “Adopt the pace of nature: her secret is patience.” The answers that we all seek will likely be given in sufficient time.