Akiko Iwasaki talks about mucosal immunity

Akiko Iwasaki is a Professor of Immunology at Yale and a former student in my department (Dept. of Biochemistry, University of Toronto). She got her undergraduate degree in biochemistry in the mid-1990s¹ and then did her Ph.D. in the Dept. of Imunology under my friend and colleague Brian Barber.

Alex Pallazzo is a keen podcast listener and he alerted me to an interview with Akiko Iwasaki on the EMBO podcast channel: The Right Place at the Right time. There are several reasons why listening to this podcast is worthwhile if you are interested in science and immunology. The most important reason is that it gives you a good idea of the depth of knowledge in the field because the level of the interview is pitched at those who have a considerable understanding of imunology. I'm not one of those people but I recognize good science when I hear it.

Another reason is that she discusses COVID-19 and how vaccines work. As you know from earlier posts, the serum antibody levels induced by the current vaccines wane after a few months so that vaccinated people can get infected by the SARS-CoV-2 virus. The secondary response then kicks in protecting you from serious illness. In order to stop the initial infections and prevent the spread of the virus we might have to get booster shots every six months or so and that's not a satisfactory solution.

Iwasaki works on something called mucosal immunity, which is new to me but very familiar to the experts. Here's a brief description from her website and a figure from Wikipedia.

The mucosal surfaces represent major sites of entry for numerous infectious agents. Consequently, the vast mucosal surfaces are intricately lined with cells and lymphoid organs specialized in providing protective antibody and cellular immunity. One of the most fundamental issues in this field concerns how antigens in the mucosa are taken up, processed, and presented by antigen presenting cells. Our laboratory's goal is to understand how immunity is initiated and maintained at the mucosal surfaces, particularly by the dendritic cells (DCs), through natural portals of entry for pathogens that are of significant health concerns in the world.

We focus on understanding how viruses are recognized (innate immunity) and how that information is used to generate protective adaptive immunity.

I hope I understand this well enough to explain it in simple terms. Mucosal immunity means that there are IgA antibodies in the mucosa that surrounds cells in certain parts of the body. For our purposes, the cells in the respiratory tract are important in COVID-19. The memory B-cells and T-cells that respond to the antigen are located right under the mucosa. Imagine that you could produce a vaccine that induced IgA against SARS-CoV-2 in the mucosa. The antibodies would be located right where the virus enters the body and they don't disappear over time like IgG in the blood stream. Furthermore, the secondary response is induced right near the site where the virus is attacking the body.

I think you need a nasal/throat spray vaccine to make this work and such vaccines are under development. They would probably have to be given in conjunction with the intra-muscular mRNA vaccines. I wish I could get Brian Barber to explain this but I can't seem to contact him. He gave a short lesson in immunology on his daughter, Jill Barber's Instagram account last year so I know he could do it.

I learned one other thing from listening to Akiko Iwasaki. We know that SARS-CoV-2 is more virulent in cold weather, especially during the winter months. She explains that the mucosal layer needs to be kept moist but during the winter months it can dry up due to the low humidity. The outside air is cold, therefore the humidity is low, and we import that air into our homes and workplaces. This dry air promotes spread of the virus.

Maybe we should be installing extra humidifiers to keep the humidity at higher levels?

It's a bit of a stretch from Akiko Iwasaki to Jill Barber but we've known Jill since she was little and my wife and I are big fans so here's a musical interlude to take your mind off COVID-19.

---

1. She must have taken my Molecular biology course and that's probably why she knows so much!

What is the best COVID-19 vaccine?

Take any vaccine you can get whenever you can. Moderna is the probably the very best vaccine and Pfizer-BioNTech is a close second. AstraZenica is very good but Johnson & Johnson not so much.

A brief summary of the COVID-19 vaccines was published in the Dec. 23rd issue of Nature. It doesn't go into a lot of details but I think the overall impressions are valid. The most serious probem with the summary is that it doesn't take into account the Omicron variant.

Mallapaty, S., Callaway, E., Kozlov, M., Ledford, H., Pickrell, J. and Van Noorden, R. (2021) How COVID vaccines shaped 2021 in eight powerful charts. Nature 600:580-583. [PDF] The extraordinary vaccination of more than four billion people, and the lack of access for many others, were major forces this year — while Omicron’s arrival complicated things further.

The first graph shows the popularity of the major vaccines. It's significant for two reasons. First, people in North America don't realize that the AstraZenica vaccine has made such an enormous contribution to fighting the pandemic. That's because AstraZenica wasn't approved in the United states in spite of its effectiveness and it got a bad reputation in Canada.

Second, the Chinese vaccine, CoronaVac (also known as Sinovac), has been widely distributed throughout the world. The CoronaVac vaccine is an inactivated virus vaccine that doesn't require ultracold temperatures for storage and it is relatively cheap to manufacture. China has been vaccinating people everywhere, notably in Brazil and Indonesia. The CoronaVac vaccine was quite effective against the early variants but it doesn't work as well with the Omicron variant.

The distribution data also shows that the Pfizer-BioNTech vaccine, the one developed in Germany, is far more popular than the Moderna vaccine that was developed in the United States. Even Sinopharm, another Chinese vaccine, is more popular than Moderna. As far as most of the world is concerned, it's the German, British, and Chinese vaccines that are going to save them and not the one created in Boston.

Some of the vaccines are more effective than others but unfortunately the Nature article only addresses the vaccines that are widely used in Europe and North America. The data shows that the mRNA vaccines are very effective against all of the variants that arose before Omicron. The mRNA vaccines not only protected against symptoms but also against severe disease (hospitalizations). The AstraZenica vaccine was also very good but not quite as good as the mRNA vaccines. The Johnson & Johnson vaccine was much less effective.

These data do not address any possible side effects of these vaccines and that's important because it is widely believed in some countries that the AstrZenica vaccine poses a much higher risk of side effects. That's not true. There may be a slightly increased risk of side effects with AstraZenica but it's not significant.

The vaccine's ability to block symptoms depends on the antibody levels in the serum while the ability to prevent long-term infections depends on the development of robust memory B-cells and T-cells. As with all vaccines, the initial antibody levels fall after the vaccination so the ability to prevent initial infections by the virus wanes over time [The omicron variant evades vaccine immunity but boosters help] [On the effectiveness of vaccines].

You can see from the above graph that the vaccines' ability to prevent infecion by the Delta variant falls off considerably by six months after completing the vaccination schedule. It's important to note that this data is with the Delta variant and it explains why countries that rushed to vaccinate their population as quickly as possible in early 2021 suffered more in the Delta wave. It's why booster shots were promoted in Israel and the United States because both of those countries vaccinated early and waited only the minimal time between doses. (Other countries waited longer between the first and second doses so the waning of initial infection was delayed.)

The waning effect is even more pronounced with the Omicron variant because it arose later in the year when far more people were beyond the six month limit of primary infection protection. What this means, I think, is that the Omicron variant isn't special because it "escapes immunity"—that would have been true of any new variant just as it was true of Delta. In any case, the mRNA vaccines are better because they start with a higher level of protection and if the data is accurate it means that Moderna is better than Pfizer.

I was prompted to post this article because many Canadians are hesitant to get the Moderna vaccine for their booster shot, especially if they had Pfizer first. That's ridiculous. Moderna is probably a bit better and, besides, there's plenty of data showing that mixing vaccines is better than sticking with the same one for all your shots.

---

Image Credit: The coronavirus figure is from Alexy Solodovnikov and Wikmedia Commons.

Ontario (Canada) hospitals are filling up with fully vaccinated patients

The Omicron wave is surpassing all records for the number of cases in Ontario. The province has given up on testing for most people so the actual case counts are far higher than the reported cases and it's unlikely that the numbers are dropping in spite of what the graph (below) might suggest. Judging by what's going on in other countries, the peak is still a week or two away.

Ontario residents have been very good about getting vaccinated. As of today, 88% of eligible people over the age of 12 have been fully vaccinated and 91% have received at least one dose. The 5-11 age group became eligible about six weeks ago and so far 45% have had one shot. This places Ontario (and the rest of Canada) among the most vaccinated places in the world.

Since the unvaccinated population is only 10% of the total, this means that most of the cases are among the fully vaccinated population and most of those cases are mild or asymptomatic. Fully vaccinated people are also getting infected in other countries but the effect is often masked by a large number of cases among the unvaccinated population. This can deceive people into believing that you don't need to worry if you are fully vaccinated.

About 30% of eligible people have received a booster shot and that group is not reporting significant numbers of infections consistent with the data showing that a recent booster will protect you from gettng even mild forms of COVID-19.

It's pretty clear that the Omicron variant is being spread by people who are fully vaccinated with no booster. They may have mild symptoms but they can infect others, including young children and the elderly, who can suffer more severe symptoms.

The number of people in hospital with COVID-19 is rising sharply but so far it's still less than the numbers in the Delta wave last Fall. That's expected to change rapidly over the next few days and there's a great danger that the health care system will be overwhelmed. The best guess so far is that we will just scrape by by cancelling all elective surgeries and restricting the number of non-COVID patients who get admitted to hospital. Other countries may not be so lucky.

Given the high levels of vaccination, you might suspect that most of the people in hospital will have been fully vaccinated and that's exactly what we see. 71% of the COVID-19 patients in the hospitals have been fully vaccinated but this number is slightly misleading since it includes patients who were admitted for other reasons and subsequently tested positive for COVID-19. Those people aren't necessarily being treated for severe COVID symptoms.

It's hard to get an accurate number for the hospitalization rate because we don't know how many cases there are but it looks like that number is below 1%. This means that, on average, fewer than one patient will end up in hospital for every 100 who get COVID-19. This rate is far below the overall rate of 3.9% since the pandemic began and about 2% for the Delta wave when a substantial percentage of the population was vaccinated. It's data like this that suggest that the Omicron variant causes a milder form of COVID-19 but the data is confounded by the fact that fully vaccinated people are now getting infected whereas they still had substantial serum antibody levels during the Delta spike. I'd like to know what the hospitalization rate (and the death rate) was for unvaccinated people last year and what it is now.

The unvaccinated group makes up only 24% of the hospitalized patients but 49% of those in the intensive care units (ICU). This is clear evidence that vaccination offers significant protection against severe forms of the disease—that's exactly what vaccines are supposed to do. However, it's worth noting that 51% of the patients in the ICUs are either fully or partially vaccinated. You can still get a serious case of COVID-19 if you are fully vaccinated. As with the case numbers, this severe outcome will not be obvious in countries with lower vaccination rates and that could be a problem if you are trying to stop the spread.

---

The effect of spike protein mutations in the Omicron variant

The Omicron variant of SARS-CoV-2 contains a large number of novel mutations in the spike protein. How did these mutations occur and what is their effect on the properties of the variant?

The origin of the novel mutations

The phylogeny of the Omicron variant is unusual—it seems to have appeared without any documented history of steady accumulation of mutations. It looks like it split from the other variants before the summer of 2020. This leads to suggestions that the virus was circulating (and mutating) long before it was first detected.

One idea is that the ancestor of the Omicron variant jumped to another species and evolved in that species for 18 months before jumping back into humans. This would account for the lack of intermediates seen in screening infected patients. Several of the key mutations in the spike protein sequence are similar to variants that have adapted to bind to the mouse version of the receptor (ACE2) (Sun et al. 2021) and the Omicron spike protein binds strongly to mouse ACE2. (The original SAR-CoV-2 variants do not infect mice.) I think it's safe to conclude (tentatively) that Omicron evolved in mice and jumped back to humans in October or November 2021.

Immune evasion

The Omicron variant infects people who have been fully vaccinated or who have been previously infected with one of the other variants (Zhang et al. 2021). This is because the low level of circulating antibodies in these individuals is not sufficient to block Omicron. The level can be boosted with a booster shot (or a recent infection) and this increase protects against infections by Omicron. Fortunately, Omicron is attacked by T-cells and memory B-cells in vaccinated individuals so the infections are mild (Redd et al. 2021).

The mRNA vaccines elicit polyclonal antibodies to the spike protein of the original (Wu) variant. Some of these antibodies will recognize surface antigens that have mutated in Omicron so that's why it requires a higher concentration of antibodies to neutralize Omicron. We're lucky that boosting the overall antibody levels with a booster shot is sufficient to protect us from infection. We're also lucky that the T-cell response is robust—it didn't have to be.

The important point to remember during the Omicron wave is that the virus infects, and is transmitted by, fully vaccinated individuals (no booster). Some of the talking heads on TV seem to forget this when they advocate for keeping the schools open as long as everybody is vaccinated. That's not going to stop the spread and, besides, some of those vaccinated children are going to end up in the hospital. What they need to be telling us is that keeping schools open is going to result in X number of hospitalizations and Y number of deaths and this is an acceptable trade-off. (Parents, teachers, school bus drivers, school administrative staff, and their elderly parents may disagree.)

Transmissibility

The Omicron variant is highly transmissible, meaning that it is more infectious than the other variants. This feature explains the enormous spikes of cases in all countries that are experiencing an Omicron wave. We've not seen anything like that in previous waves.

Some of that peak might be due to the fact that vaccinated individuals are not being as careful as they should be so they are spreading the virus in their communities. That may explain the differences between different countries, or different states within a country, but it's not the full story.

Initially, there was a lot of speculation that the spike protein mutations in Omicron made it bind more strongly to the human ACE2 receptors and that would explain why the virus was more infectious. But most of those studies were based on models and the results from different groups were contradictory. Recently the Chinese scientists who have been at the leading edge of these studies since the beginning have shown that the Omicron spike protein does not bind significantly more tightly to ACE2 than the version from other variants (Zhang et al. 2021).

It looks like the increase in infectivity is due to enhanced entry of the Omicron variant into cells once it has bound to the receptor. Some of this is probably due to a mutation that creates a more favorable furin cleavage site but additional increases in entry might be due to conformational changes in the spike protein (Zhang et al. 2021)

Milder cases?

There's a lot of speculation that the Omicron variant causes less severe forms of COVID-19 but the data is complicated by the fact that vaccinated and convalescent patients are also suffering from COVID-19 and they are partially protected. I don't think it's really known whether naive (unvaccinated and not previously infected) individuals have a milder form of the disease and I know we don't have any data on the long-term effect of Omicron infection. Please let me know of any studies that have been released.

I don't know of any logical connection between the known mutations in Omicron and the severity of COVID-19.

---

Redd, A. D., Nardin, A., Kared, H., Bloch, E. M., Abel, B., Pekosz, A., Laeyendecker, O., Fehlings, M., Quinn, T. C., and Tobian, A.A. (2021) Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals. bioRxiv : the preprint server for biology, 2021.12.06.471446. [doi: 10.1101/2021.12.06.471446]

Sun, Y., Lin, W., Dong, W., and Xu, J. (2021) Origin and evolutionary analysis of the SARS-CoV-2 Omicron variant. Journal of Biosafety and Biosecurity. [doi: 10.1016/j.jobb.2021.12.001]

Wei, C., Shan, K. J., Wang, W., Zhang, S., Huan, Q., and Qian, W. (2021) Evidence for a mouse origin of the SARS-CoV-2 Omicron variant. Journal of Genetics and Genomics. [doi: 10.1016/j.jgg.2021.12.003]

Zhang, X., Wu, S., Wu, B. et al. (2021) SARS-CoV-2 Omicron strain exhibits potent capabilities for immune evasion and viral entrance. Sig Transduct Target Ther 6:430. [doi: 10.1038/s41392-021-00852-5]