Designing vaccines with reverse vaccinology

Investigating antibodies produced by infectious diseases yields vaccines with broad-acting protection.

Aug 17, 2021
Tiffany Garbutt, PhD
Designing vaccines with reverse vaccinology

Most vaccine development begins with looking at the pathogen. Scientists pinpoint key residues needed for the virus to enter the body and develop vaccines that train the body to recognize signatures of the foreign invader. Kevin O'Neil Saunders, associate professor of surgery and director of research at the Duke Human Vaccine Institute at Duke University develops vaccines after analyzing the body’s immune response to a pathogen. By understanding the antibodies produced in response to a pathogen, researchers can reverse engineer a vaccine that elicits the same response. Saunders studies the antibody responses to human immunodeficiency virus (HIV) to develop a protective HIV vaccine. 

Kevin O’Neil Saunders, PhD
Associate Professor /Director, Laboratory of Protein Expression / Director of Research / Duke Human Vaccine Institute / Department of Surgery / Duke University Medical Center

When the COVID-19 pandemic occurred, Saunders used these same principles to develop a potential pan-coronavirus vaccine. By studying antibody responses in people who previously had been infected with SARS-CoV-2, Saunders and his team identified a highly conserved region on the receptor-binding domain of the spike protein that makes coronaviruses susceptible to neutralizing antibodies. They then developed a nanoparticle vaccine, based on the naturally occurring self-assembling protein ferritin, that presented this vulnerable receptor binding domain to the body, and tested its efficiency in cynomolgus macaque monkeys. Remarkably, Saunders’ vaccine induced antibodies that neutralized SARS-CoV2 and its variants from the United Kingdom, South Africa, and Brazil (1).

What sparked the idea of a pan-coronavirus vaccine?

Our research focuses primarily on HIV vaccines. One of the main goals of an HIV vaccine is to find antibodies that bind diverse strains of the virus. We are currently working on broadly neutralizing antibodies that neutralize or inhibit many different types of HIV. When the SARS-CoV-2 pandemic began, we thought that we could take the same approach and apply it to SARS-CoV-2: study neutralizing antibodies that arise during natural infection, and then try to design a vaccine that can generate the same type of response.

What is reverse vaccinology?

Reverse vaccinology is essentially beginning with the desired immune response. We then try to design a vaccine that gives that response. That gives us a great way to evaluate the vaccine because we can specifically test whether or not the vaccine produced the right response. 

How did you develop the pan-coronavirus vaccine?

We isolated antibodies from two different individuals, one infected with SARS-CoV-2 and another infected with SARS-CoV-1. We studied the cross-reactive antibodies that blocked infection. When we studied those antibodies from the SARS-CoV-1 infected individual, we recognized that they bound to a specific site on the spike receptor binding domain. We focused a vaccine against the receptor binding domain because we knew that if we focused the immune response against that specific part of the spike protein, we would have a chance of generating a cross-reactive neutralizing antibody.

How does it work?

We arrayed multiple copies of the conserved spike protein receptor binding domain across a ferritin molecule with 24 receptor sites. Immune cells recognize foreign pathogens by looking for multiple copies of a particular part of a virus. Each immune cell has multiple receptors on its surface, and those receptors are all searching for pathogens. When we show the immune system multiple copies of a virus site, it stimulates immune cells far better than if we show the immune system only one copy. We wanted to focus the response against the receptor binding domain. We also wanted to give immune cells multiple copies to recognize. 

How do you approach designing infectious disease vaccines?

We first consider the diversity of the virus. Then we consider the best way to interact with the immune system to produce antibodies. Generating broadly reactive neutralizing antibodies is a recurrent theme across the HIV vaccine field. How to generate those antibodies differs slightly between research groups, but each of us tries to target specific neutralizing antibodies that evolve into the types of cross-reactive antibodies that we want. 

For SARS-CoV-2, it is a slightly different question. We need a protective level of antibodies. We want a response that does not solely depend on one site because the virus is an RNA virus. It will mutate, and as it mutates, sites change. At some point, the virus will escape from that vaccine. We want a response that targets multiple sites. That way, if one site changes, we still have a second site to provide protection.

What are the challenges for an HIV vaccine?

The antibody response to HIV works only against the virus used to create the vaccine. It does not cross-react against viruses circulating elsewhere in the world. The viruses that are circulating in the United States are different from those in Thailand, which are different from the those in Africa. Researchers have to deal with this diverse population of HIV. Generating an immune response against a single HIV strain is not very helpful for HIV. 

In contrast, when we immunize with SARS-CoV-2 using the Wuhan strain, we get antibodies that work against the Wuhan strain, but they also work against the Washington strain and against some newer isolates. It is a lot easier to generate a response there because the virus has not diversified itself anywhere near as much as HIV. Once the virus starts to change, it becomes harder for the vaccines to work. New SARS-CoV-2 variants have emerged over the course of a year. HIV has had more than 80 years of evolution in humans, plus multiple years of evolution in non-human primates. 

Secondly, the immune system does not make the types of antibodies needed to protect against HIV. The protective antibodies we find in infected individuals that bind to many different versions of HIV take many years of infection and occur in only about 50% of people. We need to make the immune system produce an antibody response that it does not normally make, and create that response at a really high level. We study why the immune system does not want to make these antibodies, and tailor HIV vaccines to work around that.

What is next for the pan-coronavirus vaccine?

We would like to understand the antibody response at a deeper level. To get a better sense of why this vaccine generates such a broad response, we need to isolate single antibodies and compare how similar those antibodies are to antibodies produced during infection. If we know what those antibodies are, then they become examples for the type of vaccine-induced cross-reactive antibodies that we want all of the coronavirus vaccines to elicit. 

Secondly, we are trying to move this into a clinical trial to explore whether or not humans produce the same types of cross-reactive antibodies that we saw in monkeys. 

And thirdly, we want to broaden the vaccine. There are a few bat coronaviruses that are highly similar to SARS-CoV-2 that readily attach to and enter human cells. Those viruses just need to come into contact with a human to start a new coronavirus outbreak. Having a vaccine that works against those is great, but there are far more coronaviruses out there. 

Reference

  1. Saunders, K.O. et al. Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses. Nature 594, 553-559 (2021).
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