Vaccines vs mutants

Antibodies attaching to the spikes of a coronavirus

What is a vaccine? It is either a virus that is similar to a nasty one, but not pathogenic (live, “attenuated” virus vaccine, eg the oral polio vaccine), or killed, usually with formaldehyde, or more recently just parts of the outside of the virus. In all cases the vaccine makes you produce proteins in the blood, called antibodies, that can bind onto the nasty virus and prevent it from infecting you, ie the antibodies make you “immune” to the virus. There are many different ways to produce a vaccine, each trying to overcome specific challenges. Many companies are trying to make a vaccine for covid but it takes some time because it has to be tested first to make sure it works, ie it inhibits infection by covid and it causes no serious side-effects. Usually it takes at least 4 years to design, test and scale-up a vaccine but this time the covid vaccines were produced in record time.          

            Not all viral infections can be inhibited with a vaccine. Eg there is no vaccine for the AIDS virus, in spite of many attempts, for the simple reason that the AIDS virus destroys the person’s ability to produce antibodies. In the case of covid, there were early reports of people getting infected again, but this is uncommon, although it is common with other human or animal coronaviruses. Also, people who tested positive but had no symptoms had lower amounts of antibodies than the symptomatic ones.  The short immunity seems to be because of a viral protein (Nsp1, or non-structural protein-1) that dampens the resistance of the body by inhibiting the production of interferon (an immune system protein that protects from viral infection), but there may be ways to make drug-inhibitors of Nsp1. Also, results from Southampton (England) showed that giving interferon-β directly to the lungs by inhalation helped, by replacing the interferon lost because of the infection.

            The first vaccine to be announced, consisting of the mRNA that codes for the protein of the “spike” of the virus, that projection you see on the particle, was by a company called Moderna, with headquarters in Boston, and US-NIAID. When Moderna showed that vaccinated people produced a good amount of antibodies, this was such big news that the Dow financial index shot right up! This has been record time, and this is even more impressive because these are all new technologies, never before used for vaccines…

We heard in the news that experiments of questionable ethics were performed with several vaccines to speed up the testing.  Rather than wait for people to acquire the virus naturally and show symptoms (or not, if the vaccine works), people were intentionally inoculated with small doses of covid. I hope they get paid a few million each for signing up for that, but it did not say in the news.  

            There are at least three vaccines that have been tested in phase III trials and results outlined below:

1.-   November 8, 2020:  An mRNA vaccine by Pfizer/BioNtech, a small company based in Mainz (Germany) gave a protection of  ~95% in clinical trials.

Although we don’t know yet how long the immunity offered by this vaccine lasts, it will help anyway. The vaccine needs to be kept at -80o C. It was the first to be approved and used in Canada in early December, first on health care workers, then Emergency responders, teachers, then old people, people with underlying conditions, then everybody else.

2.-  November 16, 2020:  The Moderna vaccine results are out too. It is 94.5% effective! It is very similar to the Pfizer/BioNtech one. It has the advantage that although it is mRNA too, it is not as labile, it can be kept in the fridge for up to 30 days after it is thawed. This is because it is coupled to liposomes that protect the mRNA from degradation. It needs two shots a month apart, like the Pfizer one.

For both vaccines, trials included people over 65 years old, 7,000 with the Moderna one.

            It goes without saying that a vaccine is a game changer, to get out of this nightmare that gets worse with every passing day. The Canadian government announced that ~8% of the population will be vaccinated by March 30, another 50% by June and the rest by September. Restrictions will be eased slowly during this time.   

We heard (January 13, 2021) that as of April 1, Canada will be getting a million doses a week. The aim is everybody to be vaccinated by September.  But, when people with breast cancer get it, it’s not announced yet.  Older people will go first, but no word about state of health or cancer yet, if you are not in a nursing home.

3.- An Oxford (England) company (Astra Zeneca) was already making large quantities of vaccine even before the trials showed if it works. This is a vaccine using a different approach. It uses a chimpanzee Adenovirus as a vector, where some Adenovirus genes have been removed and replaced with the gene for the covid spike protein. It gave good antibody production, but there were some problems with the Phase III trial which has to be repeated.  (Why use a chimpanzee Adenovirus as a vector? Because some people may have antibodies to human Adenoviruses that although they are harmless they may inhibit the replication of the vector).

4. January 28, 2021: Johnson & Johnson vaccine results came out. It is based on Adenovirus-26, a human virus but not as common as Adeno-5. They claim that it works with a single dose.  Phase III results showed 67% effectiveness.  But, if you get two doses then it may go up to 90% (?).  Just a guess.

5.  February 2, 2021:  The Russian vaccine phase III results are out (Sputnik). The vaccine is two Adenovirus vectors:  The first is an Adeno-26 and 21 days later an Adeno-5 vector. Trials on ~20,000 people showed a 91% efficacy, especially for people over 60. Nice!

6. February 3, 2021, Novavax vaccine:

            The Novavax vaccine is a “Protein subunit vaccine”, ie the spike protein is cloned into an insect virus (Baculovirus) vector which can produce large amounts of the protein. This approach has been used to develop vaccines against HPV (Human papilloma virus, causing cervical cancer) and Hepatitis B virus. Such vaccines however do not elicit as strong an immune response as whole virus vaccines, so they often include an adjuvant. Novavax uses a patented adjuvant called Matrix-M, which is based on a type of plant compound called a saponin (meaning “soap-like”, found very often in plants of the carnation family). The company says that this combination elicits a good immune response.

            Yesterday Prime Minister Trudeau said that Canada will be producing the Novavax vaccine in a facility in Montreal.  The building is under construction though, has not been approved by Health Canada yet, and the Novavax vaccine has not been approved either. https://www.ctvnews.ca/politics/with-novavax-deal-canada-could-be-producing-covid-19-vaccine-domestically-by-the-fall-1.5291835

Adenovirus vaccines are more stable and much cheaper to produce than the mRNA vaccines (~25$ for mRNA vaccines, $4 for Adenovirus ones). But if you get one vaccine you may make antibodies against the Adenovirus, so that you can not take another vaccine with the same Adenovirus vector. The mRNA vaccines have just the mRNA to make antibodies against, nothing else.

            Vaccines containing live virus of any kind, should not be given to immunosuppressed people, eg if you are receiving or just completed chemotherapy. The mRNA vaccines are OK to use if you are immunosuppressed, but of course you may make lower amounts of antibodies.

Of course, safety of a vaccine is important.  In September two people, out of ~30,000 that got the Astra-Zeneca vaccine came down with a serious disease of the spinal cord, called “transverse myelitis”.  However, given the circumstances it was deemed not statistically significant, so the trial continued. In another instance a man from Brazil died after inoculation, but he had received the placebo, ie he died from covid, not the vaccine.

Another company (CanSino) was a collaboration between Canada and China, but it fell through, apparently because China did not want Canada to do the testing. (Also, who knows, the Meng Wanzhou/Kovrig-Spavor-Trump affair?). Anyway, the vaccine is a recombinant of the spike gene with a human Adenovirus-5 and it performed OK but not as well as the Oxford one, likely because lots of people have antibodies to the human Adenovirus already. We’ll see.  

There are many others in trial now in the US, England, Brazil and other countries, each with their own advantages.  Some are DNA, ie more stable than RNA, some should need only one shot (Adenovirus or other viral vectors, vaccinia, Adeno-Associated virus), some are OK for immunosuppressed people, some may give longer lasting immunity. For a complete list see:

The world needs billions of doses. Very early on, Canada placed orders for vaccines from Pfizer, Moderna, Astra Zeneca and another 4 companies, all together enough to vaccinate everybody 7 times over. The fear was that, when even PPE, ie masks and goggles, were snapped up by Trump right from AirCanada planes on the tarmac in China ready to fly to Toronto, by paying double the price, and the planes were diverted to New York, it might be hard to fight for a vaccine. And each passing day would mean a few hundred more dead in Canada…

Till everybody is vaccinated, testing and testing and testing, quarantining, hand-washing, masking, and keeping apart.  Not easy.   

Covid mutants

Viruses like influenza can change their RNA genome frequently, so that we need a new vaccine every year. Covid is more stable than influenza, but it does mutate. How does this happen?

As the virus replicates the enzymes copying the viral RNA have to copy all 30,000 bases of the viral RNA correctly. This is a daunting task if you think that the copying has to be precise, otherwise the proteins made will not be functional. But, everybody makes mistakes, so do the coronavirus RNA replicating enzymes. The resulting viruses are called “variants” or “mutants”. The thing to remember is that it is the fact of replicating, nothing else, that generates the mutants. It has nothing to do with how pathogenic a virus is, or if the virus was infecting a human or an animal. Mutants that have a selective advantage, ie replicate faster or infecting more tissues etc are bound to be selected for!

The original covid from China, is not the same one you will find in most corners of the world today; the D614G mutation emerged in Europe in February 2020 and quickly became the globally dominant form of the virus. The reason is that the mutation is on the spike and it makes the virus better able to attach and multiply, without causing worse symptoms. This happens very often with viruses.  

Another mutant, called A222V, spread across Europe and was linked to people’s summer holidays in Spain.

In September, another mutant was first detected in England, possibly from South Africa. This variant may be up to 70% more transmissible.  It is referred to as VUI 202012/01 (Variant Under Investigation, year 2020, month 12, variant 01), has at least 17 potentially important alterations, including deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H), as well as mutations in other genomic regions. The N501Y is an important change because it is situated exactly at the spot that the spike makes contact with the ACE2 receptor on the cell (see photo below).

By November around a quarter of cases in London were the new variant. This reached nearly two-thirds of cases by mid-December. There are indications of a more widespread occurrence of cases across England, as well as small numbers of cases detected in other countries, including Denmark and the Netherlands, even Japan. Two cases were found in Toronto on December 26.

Where did this mutant come from? The variant is unusually highly mutated. The most likely explanation is that the variant has emerged in a patient with a weakened immune system that was unable to beat the virus. For this reason their body became a breeding ground for the virus to mutate. Of course, it is also possible that the mutant arose in an area of high incidence, eg in London (England).

Another mutation – a H69/V70 deletion, in which a small part of the spike is removed – has emerged several times before, including famously in infected mink. This mutation increases infectivity two-fold in lab experiments.  

There is no evidence to suggest that the 614 mutation makes the virus more deadly. However, just increasing transmission would be enough to cause serious problems, especially give the opportunity to the virus to mutate even more. Still, the variant from England does cause worse symptoms AND is able to spread faster.  This is why the WHO recommended to use double masks…

Illustration of the variant found in England. The viral spike (red) must fit in the ACE2 receptor of the cell (blue). Mutations help the virus bind more tightly.

March 11, 2021, anniversary of the day that WHO proclaimed a pandemic:  Data show that the new variant from England is not only able to spread faster but also more lethal than the original version.  The original virus is lethal in ~2.1% of infections, the new one is lethal in up to 4.5% of infections!  There are several thousand cases in Canada already (at least 5% in Kingston, as of March 18, 2021), so hurry up to get the vaccine fast!  The faster the virus replicates the more it mutates and the harder it gets for the vaccines to get him.  https://www.bbc.com/news/health-55768627

Will the vaccines work against the new variant?

Almost certainly yes, or at least for now.  All three leading vaccines develop an immune response against the existing spike.  The vaccines train the immune system to attack several different parts of the virus, so even though part of the spike has mutated, the vaccines should still work.  But if we let the virus replicate and mutate, then “vaccine escape” may happen, ie the virus may change so it dodges the effect of the vaccine and can infect vaccinated people.

The worry is that this virus may be on a pathway for vaccine escape, it has taken the first couple of steps towards that. That is, to make sure we get rid of this virus, better vaccinate everybody fast, before the virus has the time to replicate and mutate more, so that the vaccine does not work anymore!

A new mutant showed up in Brazil (E484K) and is spreading fast, as it was announced in January 15. The problem is that it is in a point of the spike that makes it “bend”, therefore the antibodies may not be able to inactivate it. It is not in Canada yet, but our luck may not last, as it was found in someone in North Carolina.

Fortunately, the mRNA vaccines we have are very easy to tweak, ie just change a few bases, then scale up.  However, the present stocks of the vaccine will be useless, and scaling up the new vaccine will take some crucial weeks or months. If several variants coexist, then the vaccine can be a mixture of all.

Risk of allergic reactions from the covid mRNA vaccines:

The American College of Allergy, Asthma, and Immunology (ACAAI) has issued guidance for physicians, related to the risk of an allergic reaction following vaccination with an mRNA-based covid vaccine. They recommend that:

Patients experiencing a severe allergic reaction after getting the first shot should not receive the second shot. 

The mRNA covid vaccines should be administered in a healthcare setting where anaphylaxis can be treated. All individuals must be observed for at least 15 to 30 minutes after injection to monitor for any adverse reaction. After the first million vaccinations, the frequency of adverse reactions was ~0.56 per 1,000. On January 25 the CDC reported that regarding the Moderna mRNA vaccine, 4,041,396 first doses were administered and 10 cases of anaphylaxis were reported (2.5 cases per million). In 9 cases the symptoms appeared within 15 minutes and there were no deaths.

All anaphylactic reactions should be managed immediately with epinephrine as first-line treatment. Epipen at the ready!

            The mRNA COVID-19 vaccines should not be administered to individuals with a known history of a severe allergic reaction to any component of the vaccine. One component known to cause anaphylaxis in certain people is polyethylene glycol  (substance used as filler in ice creams too).

            People with common allergies to medications, foods, inhalants, insects and latex are no more likely than the general public to have an allergic reaction to the mRNA covid vaccines.

            These vaccines are not live vaccines and can be administered to immunocompromised patients. However, immunocompromised people may make fewer antibodies.

Reference: https://acaai.org/news/american-college-allergy-asthma-and-immunology-updates-guidance-risk-allergic-reactions-mrna

It is quite likely that another virus, coronavirus or other, may spillover from other animals (bats?) over to humans and cause a pandemic, thanks to globalization…  For this reason, vigilance is necessary ie investigating pneumonias or other infections and taking the appropriate measures once one is discovered.  Above all, be careful with air travel, keep some distance, decontaminate airplanes often, improve air cleaning and do not crowd people close together in an airplane.  Goodbye cheap flights!  Even expensive flights are now risky…

 Here is something positivehttps://www.cbc.ca/player/play/1771386435861

            Doctors around the globe noticed that fewer premature babies were born since March. This is giving us pause for thought.  Experts say it could be because pollution has gone down dramatically, or because women are not exposed to whatever other viruses that may cause premature birth (and who knows what else?), or that they may be stressed less from work and commuting, or because they may have more support at home.  Whatever it is, it is very much worth studying because the implications may be staggering!

Another piece of news from Japan:  By examining the levels of a protein in the blood, called CCL17, experts could predict at early stages after infection which patients would have a mild/moderate, and which would have a severe/critical disease. That would help hospitals a lot in managing the huge volume of patients [7].

            And yet another: There are at least four coronaviruses that cause very mild symptoms in humans. As it turns out, ~5% of the general population has antibodies to those that do react to and protect from the covid. They are against a part of the “spike” protein, called S2. Interestingly, many more children, 48%, than adults have antibodies to S2!  This may explain at least in part why children and young adults resist the infection. If we can’t get the vaccine fast enough, can we get those other corona’s to get some immunity?  I would love that, but it’s not certain that old people make as many or as good antibodies to S2 as kids.  We’ll see. But, it looks promising!

            Another piece of news: People that got sick with covid already have some immunity even if they do not have symptoms anymore. When they do get a vaccine then they produce a large amount of protective antibodies.  I suspect they may not need a second dose, save it for someone else.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00502-X/fulltext

Canada’s response to the pandemic

Soon after the news broke out about the vaccines, Prime Minister Trudeau said that there will be a delay in getting vaccines to Canada because “these companies are in England, Germany or the US, so they will serve their own people first”.  I agree, but this does not explain how come for eg the United Arab Emirates have vaccinated ~60% of their population (February 28, 2021), when in Canada the number is a paltry 2.8%. Could it be because they pay more in oil-dollars?  

 So, in Canada vaccinations started “in the first months of 2021”.  There was an uproar of course, so we were told that “Health Canada wants to examine the efficacy and safety of these vaccines before approval”, hence the delay, which sounded hollow too. Finally, vaccinations started slowly in mid-December, hoping that everybody would be vaccinated by September, 2021. However, January 15 it was announced that Pfizer had some production problems, so no vaccines for a month (at least…).  We are supposed to get a million doses a week starting in April, but the September deadline is likely to be missed. In the meantime, several hundred lives will be lost.  Even worse, if the virus mutates, we will be back to square one, it will take several months to design and scale up the new vaccine to cover everybody all over again. In short, we are at the mercy of companies, that have no big investments in Canada…

Just for the record

            This begs the question:  Canada has had quite a robust Biology/medicine/Biotechnology research ability; Banting and Best were the discoverers of insulin, and the Connaught labs in Toronto have played a very important role in the production of polio vaccines in the 1950’s.  Where did all that potential go? You can blame the free trade for this that started in the 1990’s with Mulroney. The philosophy is simple:  If you can buy a vaccine/drug/equipment from someone else, why bother developing it yourself? So, the production ability of Canada was dismantled slowly, later with Chretien, then Harper.  We have to hope that this will be a big wake-up call for Governments to start funding research again…

            I have to quote Dr Robert Stewart, past head of the Microbiology dept of Queen’s: “Politicians think that once a problem comes, you just throw money at it and it will get solved… But, it won’t, or at least not fast.  You need the research infrastructure all the time”. During these covid-times, I could not agree more!  

            In February, the construction of the Novavax production facility in Montreal was announced, but it will be useful for 2022 or later, not now.  Also, Medicago (latin for Alfalfa, the clover-like plant that animals love), a company close to Quebec city is making a subunit vaccine in a tobacco-like plant. It uses a plant bacterium to introduce the spike gene in the plant. There are other ways, eg express the spike gene in the old Tobacco Mosaic virus, the very first virus to be discovered in ~1896. Medicago makes virus-like particles with the covid-spike on the outside and some (patented) adjuvants. They announced (February 2) that their phase I/II trial was successful.  

https://globalnews.ca/news/7561871/medicago-covid19-vaccine-tobacco/

References

Number of cases and deaths:  https://www.worldometers.info/coronavirus/country/us/

*CBC news, The National, October 11, 2020.

1].  Coronavirus: Cancer patients nearly three times more likely to die of Covid-19, study says.  The Independent, April 28, 2020.  https://www.independent.co.uk/news/health/coronavirus-cancer-patient-death-rate-study-china-hubei-us-a9488481.html

2]. Stability of SARS-CoV-2 in different environmental conditions. Alex Chin et al.

Lancet Microbe 2020 Published Online April 2, 2020 https://doi.org/10.1016/ S2666-5247(20)30003-3

Correspondence:  llmpoon@hku.hk

https://www.thelancet.com/action/showPdf?pii=S2666-5247%2820%2930003-3

ice

3].  https://www.medrxiv.org/content/10.1101/2020.04.16.20067835v1

4].   Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). R. Li et al., Science 10.1126/science.abb3221 (2020). https://science.sciencemag.org/content/early/2020/03/24/science.abb3221

5].  Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Liu et al. Nature, April 27, 2020.

6].  Reducing transmission of SARS-CoV-2. Prather et al, Science, May 27, 2020

7].  Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19.  Gene. 2021 Jan 15; 766: 145145. Published online 2020 Sep 24.  doi: 10.1016/j.gene.2020.145145

8]. SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals. Lam, SD, Orengo CA et al, Scientific Reports, volume 10, article number: 16471 (2020) October 5.

9]. The effect of temperature on persistence of SARS-CoV-2 on common surfaces. Riddel S, Goldie S. Hill A, Eagles D, Drew TW. Virology Journal, volume 17, Article number 145. October 7, 2020.

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