SARS-CoV-2 vaccine--May not be possible

[tall73]

This is to give a bit of perspective on the challenges of creating a vaccine for SARS-CoV-2. There is a lot of work being done now to try to find solutions, but past attempts with SARS and MERS shows potential pitfalls.

I would think this is also part of why the testing length is anticipated to be long. They need to rule out such scenarios.

Can We Beat SARS-CoV-2? Lessons From Other Coronaviruses

SARS-CoV-1 vaccine candidates exhibited adverse side effects and even exacerbated symptoms upon viral challenge.

Efforts to develop a SARS-CoV-1 vaccine have been thwarted in the past by antibody-dependent enhancement (ADE)-mediated vaccine-induced infection aggravation.17,18 In ferrets, rMVA-S vaccines were successful in inducing a rapid memory immune response, which is an essential feature of an effective prophylactic; but, when these ferrets were challenged with SARS-CoV-1, they developed enhanced liver damage.19,20 Likewise, in mice, SARS-CoV-1 vaccines utilizing either live SARS-CoV-1 or DNA-based S-protein were able to induce antibody formation and protection against SARS-CoV-1;21,22 however, challenged mice exhibited Th2-type immunopathology suggesting hypersensitivity to SARS-CoV-1 components.23 These results suggest that comprehensive evaluation of target SARS-CoV-2 signatures is required before vaccine trials ensue in humans, so as to prevent organ damage upon viral challenge. Specifically, scientists must identify different viral proteins or anti-Spike sera concentrations which would not induce ADE.

Some examples of the above:

Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus

These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.

https://www.tandfonline.com/doi/full/10.1080/21645515.2016.1177688

The implication of the current study is that application of an inactivated MERS-CoV vaccine for prevention of MERS in humans may carry a risk for lung immunopathology if subsequently exposed to MERS-CoV. The study also leads us to suggest that the extensive background of preclinical experience with inactivated SARS-CoV vaccines may be applicable to inactivated MERS-CoV vaccines.

 

[tall73]

This article gives an overview of coronavirus
properties, and the vaccine development process.


SARS-CoV-2 Vaccines: Status Report

SARS-CoV-2 Vaccines: Status Report

Several vaccines for SARS-CoV-1 were developed and tested in animal models, including recombinant S-protein-based vaccines, attenuated and whole inactivated vaccines, and vectored vaccines (Roper and Rehm, 2009). Most of these vaccines protect animals from challenge with SARS-CoV-1, although many do not induce sterilizing immunity. In some cases, vaccination with the live virus results in complications, including lung damage and infiltration of eosinophils in a mouse model (e.g., Bolles et al., 2011, Tseng et al., 2012) and liver damage in ferrets (e.g., Weingartl et al., 2004). In another study, vaccination with inactivated SARS-CoV-1 led to enhancement of disease in one NHP, whereas it protected 3 animals from challenge (Wang et al., 2016). The same study identified certain epitopes on the S protein as protective, whereas immunity to others seemed to be enhancing disease. However, in almost all cases, vaccination is associated with greater survival, reduced virus titers, and/or less morbidity compared with that in unvaccinated animals. Similar findings have been reported for MERS-CoV vaccines (Agrawal et al., 2016, Houser et al., 2017). Therefore, whereas vaccines for related coronaviruses are efficacious in animal models, we need to ensure that the vaccines, which are developed for SARS-CoV-2, are sufficiently safe.

Another consideration for effective coronavirus vaccine development might be waning of the antibody response. Infection with human coronaviruses does not always induce long-lived antibody responses, and re-infection of an individual with the same virus is possible after an extended period of time (but only in a fraction of individuals and resulting in mild or no symtpoms), as shown in human challenge studies (Callow et al., 1990). Antibody titers in individuals that survived SARS-CoV-1 or MERS-CoV infections often waned after 2–3 years (Liu et al., 2006, Wu et al., 2007) or were weak initially (Choe et al., 2017). Despite that, re-infections are unlikely in the short term. Of note, re-infections after days of recovery have been reported recently but appear to be the consequences of false negative test results (Lan et al., 2020b). However, they could happen when humoral immunity wanes over months and years. An effective SARS-CoV-2 vaccine will need to overcome these issues to protect in a scenario in which the virus becomes endemic and causes recurrent seasonal epidemics.

Understanding the Time Frames
Why does this take so long? As mentioned earlier, there are currently no approved human coronavirus vaccines. In addition, many technologies used (production platforms, vectors, etc.) are new and need to be tested thoroughly for safety. The target for the vaccine, the S protein, has been identified, and vaccine candidates are being generated. This is usually followed by two important steps that are typically needed before bringing a vaccine into clinical trials. First, the vaccine is tested in appropriate animal models to see whether it is protective. However, animal models for SARS-CoV-2 might be difficult to develop. The virus does not grow in wild-type mice and only induced mild disease in transgenic animals expressing human ACE2 (Bao et al., 2020). Other potential animal models include ferrets and NHPs, for which pathogenicity studies are ongoing. Even in the absence of an animal model that replicates human disease, it is possible to evaluate the vaccine because serum from vaccinated animals can be tested in in vitro neutralization assays. Post-challenge safety data should also be collected in these cases to assess for complications such as the ones seen SARS-CoV-1 and MERS-CoV vaccines. Second, vaccines need to be tested for toxicity in animals, e.g., in rabbits. Usually, viral challenge is not part of this process, because only the safety of the vaccine will be evaluated.

 

[tall73]

When will a COVID-19 vaccine be ready? | Live Science

The first COVID-19 vaccine to enter clinical trials in the United States, for example, uses a genetic molecule called mRNA as its base. Scientists generate the mRNA in the lab and, rather than directly injecting SARS-CoV-2 into patients, instead introduce this mRNA. By design, the vaccine should prompt human cells to build proteins found on the virus' surface and thus trigger a protective immune response against the coronavirus. Other groups aim to use related genetic material, including RNA and DNA, to build similar vaccines that would interfere with an earlier step in the protein construction process.

But there's one big hurdle for mRNA vaccines. We can't be sure they will work.

As of yet, no vaccine built from a germs' genetic material has ever earned approval, Bert Jacobs, a professor of virology at Arizona State University and member of the ASU Biodesign Institute's Center for Immunotherapy, Vaccines and Virotherapy, told Live Science. Despite the technology having existed for almost 30 years, RNA and DNA vaccines have not yet matched the protective power of existing vaccines,


"One of the things you have to be careful of when you're dealing with a coronavirus is the possibility of enhancement," Fauci said in an interview with the journal JAMA on April 8. Some vaccines cause a dangerous phenomenon known as antibody dependent enhancement (AED), which paradoxically leaves the body more vulnerable to severe illness after inoculation.

Candidate vaccines for dengue virus, for example, have generated low levels of antibodies that guide the virus to vulnerable cells, rather than destroying the pathogen on sight, Stat News reported. Coronavirus vaccines for animal diseases and the human illness SARS triggered similar effects in animals, so there's some concern that a candidate vaccine for SARS-CoV-2 might do the same, according to an opinion piece published March 16 in the journal Nature. Scientists should watch for signs of AED in all upcoming COVID-19 vaccine trials, Fauci said. Determining whether enhancement is occurring could happen during initial animal studies, but "it is still unclear how we will look for AED," Jacobs said.

A successful coronavirus vaccine will snuff the spread of SARS-CoV-2 by reducing the number of new people infected, Andino-Pavlovsky said. COVID-19 infections typically take hold in so-called mucosal tissues that line the upper respiratory tract, and to effectively prevent viral spread, "you need to have immunity at the site of infection, in the nose, in the upper respiratory tract," he said.

These initial hotspots of infection are easily permeated by infectious pathogens. A specialized fleet of immune cells, separate from those that patrol tissues throughout the body, are responsible for protecting these vulnerable tissues. The immune cells that protect mucosal tissue are generated by cells called lymphocytes that remain nearby, according to the textbook “Immunobiology: The Immune System in Health and Disease” (Garland Science, 2001).

"It's like your local police department," Andino-Pavlovsky told Live Science. But not all vaccines prompt a strong response from the mucosal immune system, he said. The seasonal influenza vaccine, for example, does not reliably trigger a mucosal immune response in all patients, which partly explains why some people still catch the respiratory disease after being vaccinated, he said.

Even if a COVID-19 vaccine can jumpstart the necessary immune response, researchers aren’t sure how long that immunity might last, Jacobs added. While research suggests that the coronavirus doesn't mutate quickly, "we have seasonal coronaviruses that come, year in [and] year out, and they don't change much year to year," he said. Despite hardly changing form, the four coronaviruses that cause the common cold keep infecting people — so why haven't we built up immunity?

While some existing drugs, whose safety risks doctors understand, may be repurposed as COVID-19 treatments, equivalent data does not exist for a vaccine because no coronavirus vaccine has ever entered widespread use.

 

[tall73]

Don’t bet on vaccine to protect us from Covid-19, says world health expert

Humanity will have to live with the threat of coronavirus “for the foreseeable future” and adapt accordingly because there is no guarantee that a vaccine can be successfully developed, one of the world’s leading experts on the disease has warned.

The stark message was delivered by David Nabarro, professor of global health at Imperial College, London, and an envoy for the World Health Organisation on Covid-19, as the number of UK hospital deaths from the virus passed 15,000.

In an interview with The Observer Nabarro said the public should not assume that a vaccine would definitely be developed soon – and would have to adapt to the ongoing threat.

“You don’t necessarily develop a vaccine that is safe and effective against every virus. Some viruses are very, very difficult when it comes to vaccine development - so for the foreseeable future, we are going to have to find ways to go about our lives with this virus as a constant threat.

 

[tall73]

When will a coronavirus vaccine be ready?

“The speed with which we have [produced these candidates] builds very much on the investment in understanding how to develop vaccines for other coronaviruses,” says Richard Hatchett, CEO of the Oslo-based nonprofit the Coalition for Epidemic Preparedness Innovations (Cepi), which is leading efforts to finance and coordinate Covid-19 vaccine development.

Traditionally, immunisation has been achieved using live, weakened forms of the virus, or part or whole of the virus once it has been inactivated by heat or chemicals. These methods have drawbacks. The live form can continue to evolve in the host, for example, potentially recapturing some of its virulence and making the recipient sick, while higher or repeat doses of the inactivated virus are required to achieve the necessary degree of protection. Some of the Covid-19 vaccine projects are using these tried-and-tested approaches, but others are using newer technology. One more recent strategy – the one that Novavax is taking, for example – constructs a “recombinant” vaccine. This involves extracting the genetic code for the protein spike on the surface of SARS-CoV-2, which is the part of the virus most likely to provoke an immune reaction in humans, and pasting it into the genome of a bacterium or yeast – forcing these micro-organisms to churn out large quantities of the protein. Other approaches, that are even newer, bypass the protein and build vaccines from the genetic instruction itself. This is the case for Moderna and a German company, CureVac, both of which are building Covid-19 vaccines out of messenger RNA.

Cepi’s original portfolio of four funded Covid-19 vaccine projects was heavily skewed towards these more innovative technologies, but it has since added four others that take more tried-and-tested approaches – including a project at the University of Oxford that uses a harmless, non-replicating virus to carry SARS-CoV-2 genetic material into the body’s cells – and it will continue to add to that portfolio. “Our experience with vaccine development is that you can’t anticipate where you’re going to stumble,” says Hatchett, meaning that diversity is key.

No vaccine made from genetic material – RNA or DNA – has been approved to date, for example. So many of the Covid-19 vaccine candidates have to be treated as brand new vaccines, and as Gellin says: “While there is a push to do things as fast as possible, it’s really important not to take shortcuts.”

“Like most vaccinologists, I don’t think this vaccine will be ready before 18 months,” says Annelies Wilder-Smith, professor of emerging infectious diseases at the London School of Hygiene and Tropical Medicine. That’s already extremely fast, and it assumes there will be no hitches.

 

[tall73]

Scientists fear the hunt for a coronavirus vaccine will fail and we will all have to live with the 'constant threat' of COVID-19

Scientists fear that it may prove impossible to produce a working coronavirus vaccine and believe the world may have to simply learn to adapt to the permanent threat of COVID-19.

The UK's Chief Medical Officer, Christopher Whitty, told a Parliamentary committee on Friday that there was "concerning" evidence suggesting that it may not be possible to stimulate immunity to the virus.

"The first question we do not know is 'do you get natural immunity to this disease if you have had it, for a prolonged period of time?'" Whitty said.

"Now if we don't then it doesn't make a vaccine impossible but it makes it much less likely and we simply don't know yet.

Doubts about the possibility of a viable vaccine are based largely on the fact that no vaccine has ever been approved for use in the US or UK against other forms of coronavirus.

Whitty told the committee the evidence from other forms of coronavirus was that "immunity [to the virus] wanes relatively quickly."

In a statement about plans by some governments to introduce so-called "immunity passports," for those previously infected with the virus the organisation said in a statement that: "there is currently no evidence that people who have recovered from COVID-19 and have antibodies are protected from a second infection."

 

[Ana the Ist]

Lol not a very popular thread, is it?

 

[tall73]

Lol not a very popular thread, is it?

Not a popular topic! And I suppose looking back I probably should have started with the news sources and then gone to the more technical. But six people found it informative.

I think some are counting on the vaccine, and I am not sure all realize how much of a long shot it is.

 

[Petros2015]

I think some are counting on the vaccine, and I am not sure all realize how much of a long shot it is.

I kind of just skimmed this but there might be a bigger problem.

So... basically what we are saying is, when we tried to develop SARS vaccines it creates anti-bodies, but when the virus shows up, the anti-bodies behave too aggressively and damage organs?

Do you see the potential 'Second Wave' problem? All those 'asymptomatic/mild cases' that got exposure on wave #1 and didn't know it and created anti-bodies...

Kinda like... if you are allergic to bee stings. You develop an allergic response that is too aggressive the first time you are stung, but don't realize it and shrug it off. The NEXT time you get stung, the response that was built from the first time kicks in, but it is WAAYYY too aggressive, and now you are in danger from your own body's response.

This could get fun.

 

[tall73]

I kind of just skimmed this but there might be a bigger problem.

So... basically what we are saying is, when we tried to develop SARS vaccines it creates anti-bodies, but when the virus shows up, the anti-bodies behave too aggressively and damage organs?

Do you see the potential 'Second Wave' problem? All those 'asymptomatic/mild cases' that got exposure on wave #1 and didn't know it and created anti-bodies...

Kinda like... if you are allergic to bee stings. You develop an allergic response that it too aggressive the first time you are stung, but don't realize it and shrug it off. The NEXT time you get stung, the response that was built from the first time kicks in, but it is WAAYYY too aggressive, and now you are in danger from your own body's response.

This could get fun.

I did wonder if SARS vaccines cause such a reaction on challenge, how would that differ from re-infection. I am not sure we know yet.

 

[Ana the Ist]

Not a popular topic! And I suppose looking back I probably should have started with the news sources and then gone to the more technical. But six people found it informative.

I think some are counting on the vaccine, and I am not sure all realize how much of a long shot it is.

Virus vaccines are almost always tricky...especially ones that mutate as quickly as Covid. I mean, herpes has been around forever and there's no vaccine for that. I think the chances of a vaccine are slim....and even less so for a vaccine anytime soon.

 

[Petros2015]

Yeah, particularly for Coronavirus type viruses - are there *any* Coronavirus vaccines?

Human cold, coronavirus - Nope
HIV, coronavirus - Nope
SARS 2003, coronavirus - Nope
MERS 2012, coronavirus - Nope

"Doubts about the possibility of a viable vaccine are based largely on the fact that no vaccine has ever been approved for use in the US or UK against other forms of coronavirus."

Covid-19, coronavirus - Oh sure, just hang we'll have it ready in a few months... *behind the scenes sweating nervously*

Granted, our med-tech improves quite a bit every year, I'm not saying it can't be done when every lab internationally leverages the global infrastructure and works on it as a priority #1 problem, which they will in this case. But there's a public perception that it's easy because pretty much every hollywood pandemic film ends with someone magically creating and distributing a vaccine globally over the weekend.

It don't work like that.

First thing my fiance' said when I showed her the Wuhan news clips in late Jan and said 'this could be a problem' was to dismiss it and say 'oh they'll make a vaccine'.

Uh... nope.

 

[Petros2015]

Also, you might want to read this - this is the roadmap GW left behind in 2006 to follow in case of something like this. It includes guidance on, 'if there were a vaccine, it will be in limited supply, so who gets it first'

https://www.cdc.gov/flu/pandemic-resources/pdf/pandemic-influenza-implementation.pdf

Probably a lot of other good info in there, its the only guidance the current admin has to work with. They may not stick with it entirely, but they probably won't deviate from it much if it doesn't make sense to.

I'm expecting that if there is a vaccine, I will have to take a number. And the number may be large.
Which is fine, EMTs and others are more essential that me, I'm OK with that. It helps me to set my expectations appropriately. But a lot of other people will be screaming and shouting 'Me! Me! ME!!!" lol. Inappropriately set expectations. But, my expectations about their inappropriately set expectations are also set and have been for some time.

 

[sfs]

Human cold, coronavirus - Nope
HIV, coronavirus - Nope

HIV isn't a coronavirus. I don't think anyone has seriously tried to develop a vaccine against cold viruses, and SARS and MERS vaccine efforts were largely shelved.

 

[sfs]

Virus vaccines are almost always tricky...especially ones that mutate as quickly as Covid.

SARS-CoV-2 doesn't mutate particularly quickly, at least not for an RNA virus.

 

[Ana the Ist]

SARS-CoV-2 doesn't mutate particularly quickly, at least not for an RNA virus.

Aren't there already 30+ strains of covid19?

 

[tall73]

Aren't there already 30+ strains of covid19?

Compared to influenza other coronavirus examples mutate more slowly. I suppose this could be different, but we will have to see. Depending on what the immune response is directed towards small mutations may not matter much, other than helping to track which cases came from where.

 

[sfs]

Aren't there already 30+ strains of covid19?

Depends on what you mean by 'strain'. There have been lots of mutations; which ones, if any, cause the virus to behave differently is still largely an open question. A good (and rather lengthy) summary of what was known as of a week ago is here.

 

[hedrick]

maybe, maybe not. I'm always skeptical when people say things can't be done. I do understand there are problems, but lots of people are trying lots of approaches.

In Race for a Coronavirus Vaccine, an Oxford Group Leaps Ahead

It would be a big help even if immunity doesn't last forever.

 

[tall73]

maybe, maybe not. I'm always skeptical when people say things can't be done.

The title used to talk about the difficulty....but this title brought more traffic. I suppose even forum posters need more extreme titles to get clicks these days!