Nearly half a million Israelis so far have received another vaccination – their fourth in the past year. It's hard to imagine that anyone – the general public, the medical community or even the vaccine makers themselves – would have predicted such a scenario a little over a year ago when COVID vaccines were first authorized and the global vaccination campaign began.
The team of experts advising the World Health Organization on the COVID vaccines issued a statement this week saying that a vaccine strategy based on repeated booster doses that based on the original vaccine is unlikely to be sustainable. They once more stressed the importance of vaccinating countries that are not yet immunized and advocated for equality and making vaccines more accessible to poorer countries in order to achieve world public health targets.
The WHO experts also noted that the COVID vaccines are very effective at preventing infection and the spread of infection, in addition to preventing severe illness and death. They said their continued development is vital and that as the virus continues to evolve, it may be necessary to update the current vaccines to ensure that they continue to provide the highest level of protection, both against omicron and any future variants.
At a press briefing held by the European Medicines Agency in Holland this week, Dr. Marco Cavaleri, the agency’s Head of Biological Health Threats and Vaccines Strategy, said that a second booster could be a contingency measure but that repeated, frequent vaccination was not viable in the long-term.
“We haven’t seen data yet regarding a fourth dose, and we want to have this data before we can make a recommendation. But we are also quite concerned about a strategy that entails repeated vaccinations within short periods of time… we need to see what will be the best strategy for vaccination in the long-term,” Cavaleri said.
He went on two cite two main concerns about giving a booster every four months. “We will end up potentially having problems with immune response, and immune response may end up not being as good as we would like it to be, thus we must take care not to overload the immune system with repeated vaccines. Secondly, of course, there is the risk of fatiguing the population with the continuous administration of boosters,” he said.
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These messages from the WHO and EMA about vaccine strategy echo questions the public has about the immunization strategy – first of all, about whether we are just at the onset of a future of receiving frequent booster shots and, if so, what good will this do if the virus is constantly changing?
“The vaccines are really not the only solution to pandemics. We benefited greatly because they proved to be very effective and worked as needed in the beginning and we’ve used them as much as possible. But in principle, at least among virologists and epidemiologists, the presumption is that several layers of protection are needed – the ‘Swiss cheese’ model that says every layer of protection has holes, but when you lay all the slices of cheese on top of one another, the light – or in this case, the virus – doesn’t pass through,” says Dr. Oren Kobiler, a virologist from Tel Aviv University.
The vaccine’s limited effectiveness (20-30 percent) in preventing infection with the omicron variant is one reason why health organizations are skeptical of the booster strategy as the way to stop the pandemic. “Generally speaking, vaccines do not prevent infection, but they prevent serious illness. With other viruses, too. I believe that, with the exception of papilloma, we don’t know of any vaccine that prevents infection. The flu vaccine also prevents infection to a certain degree, but it is much more effective in preventing serious illness. The coronavirus vaccines provide good protection from serious illness. The problem is that in the first months, they worked quite well in preventing infections and we all got hooked on that because it created the feeling that there was no longer a need for restrictions and other measures. But it’s not right to bring the immune system to a state of maximum antibodies all the time because it is not supposed to be in that state,” Kobiler says.
“When you look at respiratory viruses in general, you see that the contribution of the vaccine is limited or nonexistent. In a very good year, the flu vaccine is 70-percent effective, and flu is not as contagious as COVID. For respiratory illnesses like RSV and others, we don’t have a good vaccine, aside from one for measles, which is not only a respiratory virus. So we have a big problem, because COVID is respiratory and the level of protection the vaccine needs to give in order to prevent infection is very high and this is very hard to achieve. So even if there will be a vaccine that is tailored to omicron, it will provide good protection from omicron for three to four months. But who knows how it will react to the next variant, which could be closer to delta in its composition and able to evade it more easily,” Kobiler says.
He believes the solution does not lie in giving more and more booster shots, but in a more concerted effort to limit contacts and gatherings in order to reduce the rate of the pandemic’s spread while vaccinating those who have yet to be immunized at all. “Immunizing the whole world with a first and second vaccine is more important than repeatedly inoculating those who have already had the vaccine,” he maintains.
One thing the EMA vaccine chief said that drew a lot of attention was that repeated vaccination could potentially overload the immune system and even lead to a less effective immune response.
Kobiler thinks there is no real risk of this, even with repeated boosters. “The immune system is able to deal with viruses time after time within short periods of time. There are viruses we cope with several times a year and it doesn’t do any harm,” he says.
“Theoretically, it’s true that if the repetition occurs at a very high frequency it could suppress the immune response a little and cause it to focus too much on the profile of a specific variant until it gives up and says: I don’t need to respond so strongly to this. But that’s definitely not going to happen with a fourth or fifth dose. Maybe if we were really to start systematically giving a vaccine every month or two. And even then, that’s based mainly on immunological theories and experiments that were done with mice. We don’t know how it will react in humans,” he says.
Professor Jonathan Gershoni, an immunologist from Tel Aviv University, thinks the fear of harm to the immune system or to the immune response due to the second booster (the fourth shot) is farfetched.
“There’s something we call ‘immune system tolerance” – part of the ‘education’ of the immune system. These are clear and natural molecular processes through which the immune system learns to differentiate between self-proteins and non-self-proteins, so the body will know what to defend itself against, and so it won’t attack itself. Part of this is developing the ability to withstand this or that antigen. There are theoretical situations, in experimental systems, where if there is overload over time, it could eventually lead to a degree of indifference on the part of the immune system. This is a theoretical argument, and it does not apply to this situation. To say it applies to four shots a year is going way overboard.”
Gershoni continues, “People are counting shots, but when you’re talking about overload you have to talk about the dosage of the immunizing material. The Moderna vaccines, for example, are given in dosages of 100 micrograms per dose, and the Pfizer vaccines in 30 micrograms for adults (and 10 micrograms for children) – meaning that someone who received three doses of Moderna (two vaccines and a booster) received 300 micrograms of the immunizing substance, while I, having received four doses of the Pfizer vaccine in the past year, received just 120 micrograms in total. And the third Moderna shot showed the same ability to raise the level of antibodies even after a larger ‘load.’ I believe there is nothing to fear from a fourth vaccine and that the anticipated benefit far outweighs the theoretical concern.”
Each virus is a world unto itself
Given the varying effectiveness of the vaccine in the face of new variants of the virus, and the fading of antibodies after time, can all the knowledge and experience that has been gained about the immune system, vaccines and viruses still provide us with good answers in real time?
“The world of viruses is a vast world that contains numerous families of viruses with different characteristics: non-envelope viruses, viruses with positive or negative RNA compared to DNA, viruses that are more aggressive or less aggressive. Each virus and family of viruses is a world unto itself. We know that infection with some viruses, like measles or mumps, leads to the immunity we all want, to effective lifelong protection,” Gershoni says.
He says that when you focus on the family of coronaviruses, the differences between the various strains are dramatic. “There are seven strains of coronavirus that infect humans. Four of them cause relatively mild illness – what we call ‘a cold.’ About 30 percent of colds are caused by infection with these coronaviruses. These are viruses that cause a mild cold, that one can become infected with again and again, unlike diseases like measles or chicken pox, where one infection immunizes the person for life. The four mild coronaviruses are evidently easily handled by our immune system, so that we recover from them before we establish a long-term immune memory,” he explains.
Two other viruses from the coronavirus family are much more dangerous and lethal – SARS-CoV, which erupted in China in 2002 and caused 8,000 infections and 750 fatalities, and the MERS-CoV, which first erupted in 2012 and still infects 20-50 people a year, with a 35-percent fatality rate!
“Before the current coronavirus – SARS-CoV-2 – we never examined the effect or effectiveness of a vaccine against any coronavirus. No vaccine was ever developed against the mild strains, and the two lethal strains appeared for just a short time and are must less contagious. This is the first time that we are contending with an aggressive and widespread worldwide pandemic from a coronavirus. Our frustration may derive from our lack of understanding and experience versus viruses from the coronavirus family – we end up comparing them to other viruses which we are more familiar with, but which belong to other families. It’s possible that, unlike with other viruses, with the coronavirus it is harder to establish ongoing immunity,” Gershoni says. “Nevertheless, we should be very grateful for the protection the vaccine provides from serious illness, hospitalization and life-threatening illness.”
The question remains: What can change in the vaccination process at this stage, and will adapting the vaccine to the most common variant really change the picture?
“With the flu, you get a new vaccine each time that is adapted to specific strains. Right now, COVID is not behaving in a seasonal way and we don’t know where the next strain will come from,” says Professor Tomer Hertz of Ben-Gurion University’s Department of Microbiology, Immunology and Genetics.
Updating the vaccine to adapt it to the omicron variant might seem obvious, but therein lies a trap, too. “The thought that you’ll develop immunity to a certain strain is problematic, because then another strain will appear. If you would have developed a vaccine adapted to the delta strain it would have been further from omicron. Antigenically, delta and omicron appear to be far apart. You can always only develop vaccines for what you know. Updating the vaccine also has an immunological effect. You’re trying to shift the antibodies in a certain direction that better fits the strain you’re immunizing against. The problem, of course, is that we don’t necessarily know where we’re headed,” he says.
“I think that ultimately, from what we know from history about other viruses, we’ll reach a point when the virus becomes seasonal. That is what happens. But how long will it take? That’s a lot harder to say, and it also has to do with how immunized the world as a whole is,” Hertz says.
Kobiler also thinks that COVID will become seasonal, but that frequent inoculation is not the way forward. “I am very opposed to the idea of giving more and more vaccines. I think it should be possible to get vaccinated every year along with the flu vaccine as winter approaches because I think it will become increasingly seasonal and then we’ll need to be vaccinated each year. I don’t think that vaccination every four months is the way to deal with the pandemic,” he says.
Dr. Dorit Nitzan, the WHO Emergency Director for the European Region, says “Of course, it’s best to be immunized with an effective vaccine when you encounter the virus, and it would be wonderful if we reached herd immunity. But we are far from that happening. You have to remember that the virus is also in the animal world too. All of humanity has to have immunity for the virus to change and become a very weakened virus. Right now, the majority of humanity has yet to encounter the virus or the vaccine.”