Search for a vaccine: SARS vs SARS-CoV-2 antibody responses
As the outbreak of COVID-19, which is caused by the SARS-CoV-2 virus, continues to spread globally, the race to produce an effective vaccine is underway.
One of the many researchers making important contributions to the effort is Dr Nicholas Wu (Croucher Fellowship 2015) at The Scripps Research Institute in California, though he insisted the race was against the virus, not other scientists. Indeed, given the considerable pressure, he and his colleagues have been working long hours since switching all his research efforts to COVID-19 in early January 2020.
Wu's research interests include virus evolution, structural biology, and high-throughput methodologies. At Scripps, he has been working with Dr Ian Wilson and Dr Andrew Ward as a research associate. But at the time that news of the coronavirus broke, Wu was actually in the process of winding down his research activities in preparation for starting a new position later this year, as an assistant professor in the Department of Biochemistry at the University of Illinois at Urbana-Champaign.
Wu said he took the decision to focus on SARS-CoV-2 of his own volition, entering into a collaboration with Dr Chris Mok at the University of Hong Kong’s School of Public Health after Mok asked him to become involved. Although influenza and SARS-COV-2 are a different family of RNA viruses, Wu explained, his previous research accomplishments on influenza virus and vaccines gave him a firm foundation to investigate SARS-CoV-2.
One lesson from influenza immunology is that there are many different subtypes of the virus (for example, H1 H3, H7) that are genetically different. This means an immune response elicited by one influenza subtype does not necessarily confer protection against another subtype.
“Conceptually, one important difference was that influenza already has a vaccine. The goal is a universal one-shot vaccine for all subtypes of influenza. But for the new COVID-19 vaccine, we are not looking at the breadth, we just want a vaccine that will work now,” he said.
Existing knowledge of SARS suggests that one fundamental difference in the biology between influenza and SARS-CoV-2 may be that the latter will not mutate as quickly. This may change in the future, but for now scientists are just trying to tackle what they see in front of them.
SARS and SARS-CoV-2 are about 80 per cent identical at genome level, Wu said. One rapid way to identify a therapeutic candidate is to look at existing antibodies for SARS and investigate whether they can also protect against the new virus.
“A fundamental issue about any virus is its antigenicity,” Wu said, explaining that antigenicity is essentially how the antibodies in our immune system recognise the virus.
Wu’s team and other researchers recently found that one previously known antibody from a SARS patient can actually target and recognise the new virus. Wu then used a high-resolution imaging technique called X-ray crystallography to look at the protein structure to see how that antibody recognised the new SARS-CoV-2 virus at the atomic level.
“At the moment, there is a still a lack of information on SARS-CoV-2 antibodies, but that could all change within a few weeks given the amount of work in progress,” he said. The time scale for this field of research has been greatly accelerated due to the urgency, compared with his previous work, he added.
The team’s first research findings, co-first authored by Wu, appeared as a preprint within weeks of starting the COVID-19 project and were subsequently published as an article in Science in early April 2020. The study described a crystal structure that reveals how SARS-CoV-2 is targeted by an antibody called CR3022, providing vaccine developers with structural and molecular insight into the antigenicity of SARS-CoV-2 for the first time.
A second manuscript, shared as a preprint on 17 March 2020, again with Wu as co-first author, offered additional insight with significant implications for SARS-CoV-2 vaccine development. Subject to further investigation, it revealed the possibility that antibody responses elicited by SARS-CoV-2 vaccines, which are currently being actively developed, may not always be protective.
According to Wu, the key to development of a successful vaccine in the long run is for the immune system to “recognise the common features among enemies [viruses] and attack them”. But essential to success is understanding the antibody response elicited from SARS-CoV-2 infection and how it compares to SARS.
Using plasma from patients infected by SARS-CoV-2 or SARS, and plasma obtained from infected or immunised mice, Wu’s team showed that while cross-reactivity in antibody binding to the viral protein (antigen) is common, cross-neutralisation of the live viruses is rare.
Wu explained this implies that antibody response elicited by either SARS or SARS-CoV-2 infection can often recognise the common features between the viruses but these are mostly non-neutralising antibody responses, which do not offer protection from the virus in cell culture experiments. There are two possibilities to explain this, he said.
Firstly, it may be that a non-neutralising protective mechanism can still take place in vivo but currently there is no good animal model for SARS-CoV-2 to test this. SARS-CoV-2 does not infect mice and, even if they are genetically modified, they are not good models.
The second possibility, he said, is potentially “bad news” because it could signal an antibody-dependent enhancement (ADE), which means the antibody is actually helping the virus to infect the cells.
Wu emphasised that the existence of antibody-dependent enhancement is still a hypothesis but the two hypotheses urgently need to be tested. “If antibody-dependent disease enhancement exists, the vaccine could make the disease worse in some people,” he said. This also has critical implications for vaccine design for COVID-19 and for those vaccines currently undergoing clinical trials.
Despite this caveat, Wu remains highly optimistic about on-going trials and success in the race to develop an effective vaccine.
Nicholas Wu's research interests include influenza virus, HIV, evolution, protein structure, and high-throughput methodologies. He is currently working with Dr Ian Wilson and Dr Andrew Ward at The Scripps Research Institute (TSRI) as a Research Associate. His doctoral research was supervised by Dr Ren Sun at the University of California, Los Angeles (UCLA). He will be an Assistant Professor in the Department of Biochemistry at the University of Illinois at Urbana-Champaign (UIUC) starting Fall 2020. Dr Wu received his Croucher Fellowship in 2015.
To see Dr Nicholas Wu’s Croucher profile please click here.