'I'm Working on a COVID-19 Vaccine'

I'm an infectious disease specialist and a virologist by training, and I am currently an associate professor and the director of the HIV Clinical Trials program at the Yale School of Medicine.

During my career, I have mostly focused on HIV medicine in the field of treatment and prevention. So when COVID-19 hit, thanks to this previous work, I had the machinery ready to conduct clinical trials.

From April, I led clinical trials on Remdesivir, a therapeutic drug that was granted emergency approval by the Food and Drug Administration (FDA) for treatment of COVID-19, and since August 26 I have been running trials of a vaccine for COVID-19 prevention at Yale New Haven Hospital.

The COVID-19 vaccines being tested globally are typically injectables which are being evaluated to help individuals build up an immune response; one that should hopefully protect them against COVID-19. Myself and many other scientists across the U.S. are working on the Pfizer and BioNtech vaccine, which is a messenger RNA (mRNA) vaccine.

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SARS CoV-2 is the official name of virus that causes the COVID-19 disease and the SARS CoV-2 viral antigen is the elegant spike protein—this is what many of the vaccines target. Those spikes attach to target cells in our bodies, and that's how the virus initiates infection. If you can block that attachment process of the virus to cells, that's when you can hopefully avoid infection.

The way the vaccine trial I am leading works is by using mRNA to create an antibody response to the SARS CoV-2 virus. Bodies make proteins based on what the mRNA tells it to do. Because we know the structure of the SARS CoV-2 spike protein, it has been possible to reverse engineer mRNA and cause the body to produce a non-dangerous version of this spike protein.

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The mRNA is injected into the body and gets into the cell's cytoplasm. The body then reads off the mRNA, produces spike protein structures and these are presented to the immune system. The immune system produces antibody responses against it. You now have an individual that has been exposed to, and recognized, those spike proteins as a foreign antigen before. So the hope is that if that individual is exposed to the real COVID-19 virus, the body should then attack it and avoid infection.

The phases of vaccine trials

However, when it comes to vaccines, there are no shortcuts for the three phases that we go through to ensure they are safe and effective. Fortunately, the study trial designs for COVID-19 vaccines allows for seamless transition from one phase to the next, and that has been amazing. I have observed unprecedented cooperation between academic centers, pharmaceutical companies, and biopharmacuetical companies. They are all coming together to try and get past this, rather than working in competition.

Phase one of vaccines looks at safety, trying different doses—either the amount of vaccine in a dose or the schedule in which they are administered. These phase one studies are critically important to determine whether the vaccine is safe, and provide proof of concept on its ability to produce a desired effect. Obviously the drawback of that is that you can only test the vaccine on a very small number of people for safety reasons.

Phase two is when you start to look at whether the vaccine is provoking the kind of immune responses that you want it to in a larger group. The gold standard is checking antibody levels, once the vaccine has been administered, against certain targets. Antibodies are anything you produce against a viral antigen. In the field, the benchmark tends to be that you compare the antibody response from your vaccine to the antibody levels of people who have survived COVID-19.

Phase three is larger pre-licensure studies. At this point, you have confirmed the safety and the immunogenicity (the ability to generate an immune response) from the vaccine, and now this third phase asks whether those immune responses protect against acquiring COVID-19. That's what we are now looking at. And of course, we still look at safety, because as you can imagine, we are observing a broader swathe of the population.

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A stock image of a COVID-19 vaccine. Getty/iStock

Working on the vaccine with the Black community in New Haven

I live in New Haven, Connecticut, which has a diverse community—around 33 percent of the population here are Black. Our community has a good mix of racial and ethnic minorities and as we all know, minority communities have been ravaged by COVID-19 in the U.S. There is so much evidence that Black, Hispanic and other minorities are seeing disproportionate hospitalisations and deaths.

Historically minorities are underrepresented in trials, but as we are located in a very diverse environment, many of our research programs, along with the Yale Cultural Ambassadors program, have built long standing relationships of trust with communities of color in the area that we serve.

We all know a lot of the history around mistrust due to events like the Tuskegee clinical trials—where Black males were exposed to syphilis and not provided with penicillin treatment that was available. And in the current context of the Black Lives Matter movement, where people of color feel like they are treated as lesser, I think that, understandably, those people may have their guards up when it comes to scientific research.

However, the people of color in our community who are taking part in trials, thanks to these relationships, know they are being done with the highest ethical and scientific rigour.

We have now had more than 500 people sign up for our COVID-19 vaccine trials, and though I think overall there is still only around 19 percent minorities participating in the vaccine trials nationwide, we are definitely above those average numbers here.

How the vaccine trials work

We started running our vaccine trials on August 26, and I really cannot emphasize enough that the resources needed to run a vaccine trial are enormous. We have three physicians, including myself, two registered nurses from my HIV program and at least eight to 10 additional nurses. And then we have schedulers, people who manage phone lines and data managers. And, of course, we also have administrative support from Yale School of Medicine.

I would urge people to think about the scale of funding needed to run large clinical trials involving a number of countries, and the resources it takes to be able to do that. I always say: Good ideas and potentially effective treatments can die or never be advanced simply because the infrastructure and resources to advance them through clinical development is not there.

Fortunately, we have been able to run these trials, and so when our participants come in, and we have assessed their eligibility, we administer the first dose of the vaccine. After a 30 minute period to monitor them, participants go home and can then record their symptoms in an app. That data feeds to me, as the principal investigator. If they are having a reaction, I will adjudicate if it's a vaccine reaction or a symptom that could be unrelated, and then respond to them.

Our study, like many others, is placebo controlled. One group gets a placebo and the other group gets the real vaccine, so we can rule out chance when we're looking at how effective the vaccine is. These vaccine studies are designed so that the data can be looked at even before the specified end of study—which in this case is two years. This means that if, at any point, there is a statistically significant difference between COVID-19 incidents in the vaccine versus the placebo groups, we can review the study or even submit the vaccine to regulatory bodies for consideration for emergency authorization or approval.

When will a vaccine be approved and available?

The FDA has said that it would only really look at vaccines that show at least 50 percent or greater efficacy in preventing COVID-19. Although 50 percent is not the greatest, at least it is a start. From a public health population level standpoint, decreasing the vulnerability of the population by 50 percent and potentially achieving herd immunity as a result, is a huge deal.

However, my opinion is that there are three variables that will affect when we will be able to see if this vaccine is effective. Firstly, the trials must enroll the requisite number of people, which has not been an issue. Secondly, we must wait to see the effect of two dose vaccine schedules. What we learned from the early phase trials is that the antibody response really started to skyrocket after the second dose of the vaccine. Many COVID-19 vaccine studies have a three week or 28 day wait before participants get a second dose.

Finally, and by far the most important variable, is COVID-19 incidence. If these studies are taking place in areas where there are high cases of COVID-19, you will find an endpoint early, as you will be able to gauge the efficacy of the vaccine in a population where COVID-19 is prevalent.

The data of COVID-19 incidents accruing across trials is not currently being shared, but towards the end of the year I think it will be possible to have early indicators. I think most of us would be very cautious about an extremely rapid result, and a number of pharmaceutical companies have come together to make a pledge that they would not submit any results to the FDA that they think are premature.

Because it is unprecedented to have vaccine development occur this quickly (the vaccine for the mumps, which was developed in four years, marks the record for the speed of vaccine development) we're going to learn so much. Pfizer and BioNtech are already looking to expand the phase three vaccine testing to include younger people and people with compromised immune systems, like those with HIV and, they have indicated that there is a good chance of knowing this vaccine is effective in the coming months.

But when the question is: When will an individual be able to go to their pharmacy and get a COVID-19 vaccine? Well, once we have detected efficacy of the vaccine in the trials and it meets the FDA's minimum threshold of effectiveness, the FDA will then need to evaluate it. The regulatory review process for vaccines, which are vigorous, can take some time. But in this case, I suspect it will be done on an expedited basis.

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Dr. Onyema Ogbuagu is a Yale Medicine infectious diseases specialist and associate professor of medicine at Yale School of Medicine. Ogbuagu is the principal investigator on a phase 3 vaccine trial. Yale School of Medicine/Anthony DeCarlo

I think one thing that is underappreciated is the logistics and what it takes for distribution networks to get vaccines widely available to every health system, doctors offices, pharmaceutical chains and branches.

Personally, I would predict that if a vaccine gets approval, the distribution would initially be triaged to those most at risk—people like healthcare workers, and older people and others who are most vulnerable. So, my earliest safe, super optimistic projection would be the first quarter of 2021.

It's interesting, as this is actually my sabbatical year, so working on a vaccine is exactly what I should not have been doing! But with COVID-19, I just couldn't sit on the sidelines knowing I could contribute to what has become the plague of our time.

Although we don't know if the vaccines will work yet, if they do, it will be great to be able to provide this to people. In some ways, it feels like a service to my patients and those in the communities around us. It's amazing from a scientific standpoint to be involved in the process from start to finish. But, this has been exhausting, so we all hope that COVID-19 comes to an end. It has changed our way of life and it will take many years to recover, or even get close to normal.

It couldn't feel better to be part of working solutions to prevent COVID-19. There are a lot of people working on this virus in so many ways, and it's great to be part of the frontline of scientific research into COVID-19 treatment and prevention.

Dr Onyema Ogbuagu, a graduate of University of Calabar Medical School in Nigeria, completed a Yale Medicine infectious diseases fellowship and joined the faculty of the Yale School of Medicine in 2012. He is an Associate Professor of Medicine and has conducted many HIV and COVID treatment and prevention trials domestically and internationally. Dr. Ogbuagu is the principal investigator of Pfizer and BioNTech phase 3 vaccine trial at Yale.

All views expressed in this piece are the writer's own.

As told to Jenny Haward.

'I'm Working on a COVID-19 Vaccine' | My Turn