Is targeting just the spike protein in a COVID-19 vaccine enough?

[ChinleShale]

TL;DR Summary

As I understand it the new vaccines against Covide-19 are designed to incite anummune response to the spike protein on the Sars-Cov-2 surface? Why this protein and why only one viral protein?

My impression is that the vaccines being administered in the United States - not sure about the vaccines in other countries such as the UK - create an immune reponse to the SARS-COV-2 spike protein.

Naively, one might ask why have a vaccine against a single viral protein when a virus has many proteins. Why wouldn't it be better to have a multi - protein vaccine?

This question comes from thinking about vaccines made of complete viruses such as the small pox vaccine or the Sabin polio vaccine . In these vaccines isn't the immune system on alert to several or all of the proteins in the virus rather than just one of them? Would this make a more effective vaccine? For instance, suppose the virus has a variant where one of its proteins differs so a vaccine that immunizes against protein variant A may not immunize against variant B?

 

[Ygggdrasil]

One difficulty of using whole virus for vaccines (either live attenuated vaccines or inactivated virus vaccines) is that they are slower to develop and produce because they require growing virus. Recombinant protein vaccines and mRNA vaccines are faster to develop and mass produce, though it would be much more difficult to develop these vaccines to target multiple different proteins.

 

[ChinleShale]

One difficulty of using whole virus for vaccines (either live attenuated vaccines or inactivated virus vaccines) is that they are slower to develop and produce because they require growing virus. Recombinant protein vaccines and mRNA vaccines are faster to develop and mass produce, though it would be much more difficult to develop these vaccines to target multiple different proteins.

OK. So this makes things go faster. Theoretically, would a vaccine against multiple proteins of a virus work better?

 

[Ygggdrasil]

OK. So this makes things go faster. Theoretically, would a vaccine against multiple proteins of a virus work better?

Potentially. However, SARS-CoV-2 mRNA vaccines containing only the spike protein are 95% effective, so at least for COVID-19, there's not much to gain from adding additional protein antigens to the vaccine.

 

[Jarvis323]

Summary:: As I understand it the new vaccines against Covide-19 are designed to incite anummune response to the spike protein on the Sars-Cov-2 surface? Why this protein and why only one viral protein?

My impression is that the vaccines being administered in the United States - not sure about the vaccines in other countries such as the UK - create an immune reponse to the SARS-COV-2 spike protein.

Naively, one might ask why have a vaccine against a single viral protein when a virus has many proteins. Why wouldn't it be better to have a multi - protein vaccine?

This question comes from thinking about vaccines made of complete viruses such as the small pox vaccine or the Sabin polio vaccine . In these vaccines isn't the immune system on alert to several or all of the proteins in the virus rather than just one of them? Would this make a more effective vaccine? For instance, suppose the virus has a variant where one of its proteins differs so a vaccine that immunizes against protein variant A may not immunize against variant B?

This article discusses it a little bit.

Hellerstein was also alarmed that most vaccines under development are focusing exclusively on inducing an antibody response against only one protein, or antigen, in the COVID-19 virus: the spike protein, which sits on the surface of the virus and unlocks the door into cells. But important new studies have shown that natural infection by SARS-CoV-2 stimulates a broad T-cell response against several viral proteins, not just against the spike protein.
...

These findings all call into question whether limiting a vaccine to one protein, rather than the complement of viral proteins that the body is exposed to in natural infection, will induce the same broad and long-lasting T-cell protection that is seen after natural infection.
...
Hellerstein said that he was motivated to write a review on the role of antibodies versus T-cells in protective immunity against SARS-Cov-2 when he heard from experts in vaccine development that companies would likely not be interested in testing anything beyond the antibody response. The reason given was that it would slow down the approval process or could even turn up problems with a vaccine.

https://news.berkeley.edu/2020/09/0...id-vaccine-look-beyond-antibodies-to-t-cells/

 

[ChinleShale]

@Jarvis323

I read the article and not being a biologist have some elementary questions. Pardon the ignorance.

The article says that antibody levels alone do not indicate an effective immune reaction to SARS-COV-2 and that a needed secondary indicator is T-Cell function.

- Don't helper T-cells activate B-cells to produce anti-bodies? So wouldn't high levels of anti-bodies indicate strong T-Cell activity?

- I am a bit confused about killer T-cells. I read on line that they are covered with receptors that bind to a unique antigen. are these receptors produced during T-Cell formation in the thymus or are they formed in the presence of a new antigen? So is each person born with a library of killer T-cells that bind to a menu of predetermined antigens? If so, is this menu inherited or created during development?

This question is at the same time asking why killer T-cell functioning would be more or less strong since their receptors are predetermined? If their receptors are not predetermined how do they form as part of the immune response?

- The article seems to imply that a vaccine that targets multiple virus proteins may produce longer lasting protection. But the reasoning eluded me. The one thing I got was that with multiple protein immunity, immune responses to one kind of virus could also respond to a different virus that shares some of the same proteins.

 

[Jarvis323]

@Jarvis323

I read the article and not being a biologist have some elementary questions. Pardon the ignorance.

The article says that antibody levels alone do not indicate an effective immune reaction to SARS-COV-2 and that a needed secondary indicator is T-Cell function.

- Don't helper T-cells activate B-cells to produce anti-bodies? So wouldn't high levels of anti-bodies indicate strong T-Cell activity?

- I am a bit confused about killer T-cells. I read on line that they are covered with receptors that bind to a unique antigen. are these receptors produced during T-Cell formation in the thymus or are they formed in the presence of a new antigen? So is each person born with a library of killer T-cells that bind to a menu of predetermined antigens? If so, is this menu inherited or created during development?

This question is at the same time asking why killer T-cell functioning would be more or less strong since their receptors are predetermined? If their receptors are not predetermined how do they form as part of the immune response?

- The article seems to imply that a vaccine that targets multiple virus proteins may produce longer lasting protection. But the reasoning eluded me. The one thing I got was that with multiple protein immunity, immune responses to one kind of virus could also respond to a different virus that shares some of the same proteins.

Don't worry, I'm not an expert either. I hesitate to try to answer these questions, because I don't fully understand how T cells work either. It seems that the immune system is pretty complicated, and we can't say for sure what happens without experiment. A lot of our expectations come from what happened with other viruses and vaccines. It might be easy to come to a faulty understanding based on analytic reasoning alone. I can refer the research article, if that helps.

https://www.sciencedirect.com/science/article/pii/S2590136220300231?via=ihub

Here is another paper on the subject.

https://www.nature.com/articles/s41590-020-0782-6

Based on what I've read, it would seem that one benefit of targeting multiple proteins is having redundancy, so that the virus needs more mutations to evade the immune system. In that sense, you might have more dependable long term protection, and it might be more difficult for the virus to adapt to evade the vaccine.

Sometimes it seems like antibodies play the biggest role, and other times T cells are more important. That is a major simplification. But for this virus, there is evidence that T cells are important, because antibody levels might wane fairly quickly, while memory T cells stick around. The observations of immune responses associated with less severe outcomes depending on T cells activity, and antibody levels, I don't understand. It's probably important to consider that that observation is about natural infection, where your body has no previous immunity, and is responding to the virus as it is attacking. After you get the vaccine, you have antibodies in advance of the virus attacking, and when the virus enters, it will be very small in small numbers, getting mopped up by the immune system before it gets out of hand and spreads all throughout your body.

Ultimately, we can't say for sure if the current vaccines will end up providing good long term protection. It has been reported that most of the vaccines do trigger a strong T cell response. Pfizer's vaccine was even described as triggering an 'impressive' T cell response. Compared to a 'broad spectrum' T cell response, I don't know? Whether the T cell response coming from the vaccine is narrowly targeting only the spike protein, or if it still leads to good cross reactivity with new variants, and other viruses, I don't know? It may mean, at least, that it should give some long lasting protection as long as the virus doesn't mutate too much.

As far as I can tell, so far the vaccines have been pretty successful within the scope of what they were designed to do. We are relying on the durability of the vaccine overcoming the adaptability of the virus. I guess we will find out more and more, especially now that the South African variant is spreading. They are testing whether the vaccines will work for that variant as we speak. It's worrisome because the spike protein has changed significantly. Experts are still seem to be hopeful it will still protect against that variant, at least to some extent. If we discover that the vaccine isn't effective for that variant, it will take about 6 weeks to make an updated vaccine.

 

[Laroxe]

Its not a naive question at all and in many ways the answers highlight some of the ways vaccine development has changed. The first issue is that we know that out immune system will react to foreign proteins or parts of proteins that are exposed. For an encapsulated viruses these will largely be the proteins that make up the capsule or that are outside of it, and our bodies produce antibodies that can have various effects on the target proteins.

One of the early pieces of work was to look at the antibody responses to other Coronavirus infections, there are often antibodies developed that will bind to proteins on related viruses, so called cross reactive antibodies. They identified at least 40 that bound to sites on the SARS-CoV 2 virus and tested these on this virus ability to infect cells, only 1 was identified and that was from SARS-CoV 1, which had a spike that bound to the ACE 2 receptor on cells. So as far as we know the only antibody that has a direct effect on preventing infection is to the antigens that make up this spike, the vaccines actually target more that 1. While its true for many infections that a broad antibody response is likely to be more effective, it also increases the risk of the production of aberrant antibody responses that might cause adverse effects. The methods used in developing these vaccines were already in development for particularly difficult diseases and are likely to inform most new vaccine development, they are inherently safer.

Its true that for longer lasting immunity T cell responses are necessary, in fact this virus appears to attack immune tissues in a way that interferes with these responses. All the vaccines currently in use in the west has been tested for the T cell responses and appear to generate a better response than exposure to natural infection.

The new variant identified in South Africa does have a change in one of the genes that build the spike protein but there is no evidence that this effects the vaccines effectiveness. In fact pfizer have just confirmed that their vaccine protects against this variant. This does actually show that genetic testing for tracking changes around the world is absolutely needed and totally inadequate, we only really know of these variants because of the Genomics UK (COG-UK) Consortium, which is still the only large scale monitoring service. Viruses do mutate, though the rate of these changes vary, most of these mutations will have little if any significance for vaccination or treatment, but the risk does exist. That's what created this little bundle of trouble and the same processes will create more, there are millions of viruses around, most haven't even been classified.

 

[Ygggdrasil]

The new variant identified in South Africa does have a change in one of the genes that build the spike protein but there is no evidence that this effects the vaccines effectiveness. In fact pfizer have just confirmed that their vaccine protects against this variant.

The Pfizer vaccine was confirmed to work against the N501Y mutation found in both of the new variants that were originally identified in the UK and South Africa. However, the South African variant also has a mutation at the E484 site, which has been suggested to potentially mediate escape from antibody-mediated immunity.

References (both are non-peer-reviewed pre-prints):
Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera
Xie et al. bioRxiv. Jan 7, 2021
https://www.biorxiv.org/content/10.1101/2021.01.07.425740v1

Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies
Greaney et al. bioRxiv. Jan 4, 2021
https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1

 

[Laroxe]

@Jarvis323

I read the article and not being a biologist have some elementary questions. Pardon the ignorance.

The article says that antibody levels alone do not indicate an effective immune reaction to SARS-COV-2 and that a needed secondary indicator is T-Cell function.

- Don't helper T-cells activate B-cells to produce anti-bodies? So wouldn't high levels of anti-bodies indicate strong T-Cell activity?

- I am a bit confused about killer T-cells. I read on line that they are covered with receptors that bind to a unique antigen. are these receptors produced during T-Cell formation in the thymus or are they formed in the presence of a new antigen? So is each person born with a library of killer T-cells that bind to a menu of predetermined antigens? If so, is this menu inherited or created during development?

This question is at the same time asking why killer T-cell functioning would be more or less strong since their receptors are predetermined? If their receptors are not predetermined how do they form as part of the immune response?

- The article seems to imply that a vaccine that targets multiple virus proteins may produce longer lasting protection. But the reasoning eluded me. The one thing I got was that with multiple protein immunity, immune responses to one kind of virus could also respond to a different virus that shares some of the same proteins.

You may hate me for this but I did find a very informative if long publication that works through the responses to vaccines including how the antibody response is developed and refined.
There are some qualifiers when it comes to Covid 19 in that the virus itself attacks some of the stages in the processes described, particularly in the development of germinal centres and in modifying the expression of certain chemical messengers. It also doesn't contain information about some of the new technologies used in Covid vaccines, particularly with the mRNA vaccines, which I'm sure will have an impact.
I was also thinking about the targeting of the spike protein, actually antigen presenting cells chop up this protein into smaller peptides apparently providing 4 different epitopes for our immune response to target.
I'm not sure whether I've said this before but its possible that the only reason the spike protein was chosen is that there was already a lot of work available that used this as a target in SARS-CoV 1, using that was quicker.
https://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf

 

[Ygggdrasil]

I'm not sure whether I've said this before but its possible that the only reason the spike protein was chosen is that there was already a lot of work available that used this as a target in SARS-CoV 1, using that was quicker.

No. The spike protein is the major protein on the outside of the virus and it is responsible for allowing the virus to attach to and enter host cells. Therefore, for the immune system to be able to neutralize the virus and prevent infection, it needs to produce antibodies that can bind to the spike protein and stop it from attaching to and infecting cells. Producing antibodies against other SARS-CoV-2 proteins would not be able to prevent infection in the same way that antibodies against the spike protein would. Adaptive immunity against other SARS-CoV-2 proteins could be involved in cellular immunity against the virus (i.e. through the action of killer T-cells), but various studies have shown that spike antigens are able to produce robust T-cell responses.

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On the broader issues of the immune system's response to SARS-CoV-2, the journal cell recently published a nice review article on the topic:

Adaptive immunity to SARS-CoV-2 and COVID-19
https://www.cell.com/cell/fulltext/S0092-8674(21)00007-6

Here's a relevant passage about the role of the T-cell response induced by a vaccine:

An ideal COVID-19 vaccine would elicit long-lasting high titer neutralizing antibody titers and would provide sterilizing immunity to prevent disease and onward transmission. Even if that is not accomplished, a vaccine could still be highly effective at preventing serious COVID-19 disease. If the neutralizing antibody titers are sufficient to blunt the size of the viral inoculum, the presence of memory T cells may control the infection. The working model described above (Figure 2), with severe COVID-19 cases being associated with a failure to make a T cell response fast enough during natural infection with SARS-CoV-2, is good news for vaccines, because vaccines overcome/bypass the speed problem of adaptive immunity and T cell responses. Priming of the immune system by a vaccine happens well in advance of virus exposure. Additionally, the findings that Spike is a good target for CD4+ T cell responses, Tfh cell responses, and CD8+ T cell responses in SARS-CoV-2 infected people is good news for vaccine development (Grifoni et al., 2020; Juno et al., 2020; Moderbacher et al., 2020; Peng et al., 2020), since almost all COVID-19 vaccines target Spike only.

 

[Laroxe]

No. The spike protein is the major protein on the outside of the virus and it is responsible for allowing the virus to attach to and enter host cells. Therefore, for the immune system to be able to neutralize the virus and prevent infection, it needs to produce antibodies that can bind to the spike protein and stop it from attaching to and infecting cells. Producing antibodies against other SARS-CoV-2 proteins would not be able to prevent infection in the same way that antibodies against the spike protein would. Adaptive immunity against other SARS-CoV-2 proteins could be involved in cellular immunity against the virus (i.e. through the action of killer T-cells), but various studies have shown that spike antigens are able to produce robust T-cell responses.

I'm not dismissing the importance of the spike protein, its the issue of vaccines only targeting this limited area when whole virus vaccines might produce a more effective response and this isn't an unusual view, you would indeed get a broader range of antibodies which would include the spike. Many of these might be pretty useless, but some might not be. The discussions are rather more complicated than this but it is a fact that with Covid 19 a number of new vaccine technologies were already in development allowed some researchers to build on the work they were already doing. Research had already identified the spike protein on SARS-CoV1 as an important target, these researchers got a head start with SARS-CoV2. I know with the research into cross reactive immunity with other coronaviruses, I did think that for a while that the only useful antibodies were to the spike proteins.
However what's becoming clearer is that this view is far to simple and in fact several of the vaccines in development have explicitly added to their antibody targets. A favourite currently, being the nuleocapsid proteins which appear to be involved in facilitating immunity at various levels.
https://jvi.asm.org/content/94/13/e00647-20
https://www.sciencedirect.com/science/article/pii/S0753332220311069