What the world needs is a super vaccine that can deal with all coronaviruses and future outbreaks at once. Whether that is feasible is uncertain, virologists say, “but we should at least try.”
The ideal corona vaccine is resistant in advance to future variants of SARS-CoV-2. And even better, the vaccine would work so universally that it would render all dangerous coronaviruses harmless in one fell swoop, including the ones that could potentially cause another pandemic.
Journalist Jon Cohen of Science called such a pan-coronavirus vaccine, the vaccine that offers protection against all coronaviruses, “the dream vaccine”. That dream is not new. It has been seriously considered for years, ever since the outbreak of SARS in 2002/2003. The research on it had little priority. But now that the SARS-CoV-2 pandemic keeps spawning new variants that nibble away at vaccine efficacy, the urgency is suddenly back.
“If you can build a vaccine now that protects broadly, then you’re set for a long time again,” says Marjolein Kikkert, virologist at LUMC in Leiden. “It would be fantastic if we had such a vaccine,” says virologist Berend Jan Bosch of Utrecht University. “It’s the holy grail.”
Broadly speaking, there are three possible designs for such a broad-spectrum corona vaccine. All three are being worked on in the Netherlands. The research is still at the very beginning of the development phase, carried out by academic researchers and small biotechnology companies. The big pharmaceutical companies are still waiting to see what happens: first let’s see that it works. No matter how different these new vaccine candidates are, they all revolve around the same principle: inducing resistance against a piece of the virus that all variants, or all coronaviruses, have in common.
1. Improved spike vaccines
The closest thing to reach is an improved vaccine against the spike protein, the spike-like protrusion that coronaviruses need to infect cells. The problem with current corona vaccines is that they target the part of the spike protein that is the most variable. As a result, new virus variants manage to escape previously built defenses with a few mutations each time.
The trick to preventing this is to look for parts of the spike protein that are the same in different coronaviruses, and then to offer these pieces in a vaccine. In this way, the immune system is directed to universal targets of coronaviruses.
Virologist Rogier Sanders of Amsterdam UMC previously worked on broad-spectrum vaccines against HIV, and is now using that experience to do the same for corona. There are roughly two strategies for evoking those broad-spectrum antibodies against the coronavirus spike, Sanders explains. The first is simple, he says: “You put a wide range of different spikes in the vaccine and hope that the recipient’s immune system will naturally target the common denominator, so you get what are called cross-reactive antibodies. That’s a gamble, though, because if you offer, say, six different spike proteins, you may very well elicit six completely independent antibody responses. Which then are also attenuated responses because the immune system has to deal with six different spikes at the same time.”
Sanders is about to publish the results of the first experiment with this, a combination of SARS1 and SARS2 spikes. “There we do see a cross-reactive response,” Sanders says. “In the meantime, we are now also doing experiments combining many more spike proteins. We don’t have results from that yet.”
The antibodies induced by current vaccines mainly target the head of the spike protein, especially the part that binds to the human host cell. Antibodies that act on it are effective in blocking the infection. But that part of the protein is precisely the place where coronaviruses differ greatly from one another. And it is precisely through changes at that site of the protein that variants of SARS-CoV-2 are able to escape from previously built-up immunity.
Hidden in the stalk of the spike are, however, “universal targets” that are the same in different coronaviruses. By offering such pieces of the protein in isolation in a vaccine, you can direct it so that only broad-spectrum antibodies are produced. But the trick is to find those targets, and that is the work of Berend Jan Bosch in Utrecht.
Back in 2017, long before the current pandemic began, Bosch began researching broad-spectrum antibodies to coronaviruses. “Indeed, to be able to counteract a possible outbreak, a possible pandemic,” he says. The outbreaks of SARS in 2002/2003 and MERS in 2012 had already shown that coronaviruses are not innocent.
“Antibodies can block the infection in various ways,” Bosch explains. “The most obvious is that they bind at the site where the spike protein binds to the host’s receptor.”
But antibodies can also interfere at another site, Bosch explains. While for virus binding to the cell the ‘head’ of the spike protein (S1) is indispensable, the ‘stalk’ of the spike (S2) takes care of the actual fusion of the virus with the cell, so that it penetrates. This also makes S2 a weak spot of the virus. Because there is less variation between viruses in this part of the protein, it is possible to get wider coverage. “Antibodies that bind exactly there can therefore also inhibit the virus,” Bosch says. “That’s less effective, though. So the broad coverage does come with a price.”
Bosch and his team conducted experiments with humanized mice (mice with a human immune system) that they made antibodies to spikes of several coronaviruses – MERS, SARS 1 and 2, and the common cold virus OC43. In the repertoire of antibodies in these mice, they also found two broad-spectrum antibodies. They both appeared to target a region in the stalk of the spike protein.
“The striking thing is that shortly after we published that, four or five groups came out with the finding of other antibodies but directed exactly against the same part of the spike,” Bosch says. “That shows that there are not a crazy amount of those well-conserved pieces on that S2 portion of the spike. It’s so few that I don’t think you should expect miracles from this as a target for a broad-spectrum vaccine.”
2. T-cell vaccines
Another option for getting a more broadly effective vaccine is to target its action to T cells, a type of white blood cell that plays an important role in the immune system. “Antibodies can’t look inside the cell,” says molecular biologist Gerben Zondag of the Leiden biotechnology company ImmuneTune, “but T-cells can see what’s inside the cell. This is possible because cells present bits of their contents on the outside at special receptors that can be recognized by T cells. So with a vaccine that targets T cells, you can also make other, internal virus proteins visible to the immune system.”
Together with immunologists from LUMC, Zondag’s team made such a T-cell vaccine against corona. They showed that it works at least in mice. Zondag is still looking for funding for follow-up trials in humans. His company ImmuneTune originally worked on personalized cancer vaccines based on dna. Because the laboratory was closed during the lockdown but remained open for coronagraph-related research, Zondag temporarily shifted course.
The experience with cancer vaccines gave Sunday’s team a jump start. They already had all the tools to make dna vaccines, only the recipe had to be adapted. Immune Tune’s cancer vaccine makes cells produce bits of tumor protein, which stimulates the immune system to attack and clear all cells containing this protein (i.e., the cells of the tumor). In the guise of corona vaccine, the vaccine contains pieces of dna code for virus proteins, with the intention that white blood cells learn to eliminate cells containing these proteins (i.e., virus-infected cells).
The vaccine targets a completely different protein than the spike, namely portions of the enzyme RNA polymerase, which is essential for the virus to make copies of itself. Because of that essential function, the protein is largely the same in different coronaviruses. This offers opportunities for “universal recognition” by T cells.
Zondag: “In total, we have put the code of 35 different pieces of protein in the vaccine, each 20 to 60 amino acids long. Dna is stable, so you can put a lot into it. That gives us more options than with vaccines based on proteins or rna.”
“The first results indicate that it does work, but certainly not as well as the spike-based vaccines,” says Marjolein Kikkert of the LUMC who contributed to the research on this new vaccine. A combined approach may do the trick here as well, she thinks: “I think an addition of pieces of spike is needed to strengthen the induced immunity. The vaccine should eventually be good enough to go above the threshold of 50 percent efficacy.”
On the drawing board, a nasal spray might be the ideal candidate for a broadly protective corona vaccine. Such a vaccine could, after all, induce immunity locally in the mucous membranes, precisely the place where the virus first enters the host’s body. “Looked at this way, it’s actually a bit odd that up until now we have administered vaccines against a respiratory virus in the muscle,” Marjolein Kikkert notes. The concept is promising, but this new way of vaccinating will still have to prove itself in humans.
2. Nose vaccines
There is already experience with such vaccines in the veterinary world, explains virologist Gorben Pijlman of Wageningen University: “Chicks, for example, are vaccinated against a corona virus that causes infectious bronchitis via a fine mist of nebulized vaccine. That works fine there.”
A team led by Cuban biotechnologist Luis Cruz of the LUMC in Leiden, in collaboration with the Bilthoven-based company IntraVacc, is investigating a nasal vaccine that can protect against all (future) variants of SARS-CoV-2. It is a protein vaccine, which in addition to a general piece of the spike protein also contains three pieces of internal virus proteins. The protein pieces are packaged in microscopic spheres and mixed with a protein that enhances the immune response.
The nasal vaccine should stimulate the immune system on three levels – in the production of antibodies and recognition by T cells, but also in stimulating innate defenses. The latter consists of a battery of general antiviral agents and cells that become active as soon as a virus is detected in the mucous membranes. It is the immune system’s first line of defense against invaders. “The idea of administering a vaccine there has been around for some time,” says Kikkert. “But it still has to be shown that it indeed gives better immunity. And also that can then ensure that the immunity is broader and lasts.”
Constant race for arms
Attempts enough, but will it succeed in creating a dream vaccine against corona? “A vaccine targeted against all corona viruses, that’s probably really too ambitious,” says Marjolein Kikkert. “The bottom line is that the immune system is incredibly focused on specificity. If you want to make a really good vaccine then you have to make it very specific. If you look for breadth, then you’ll still get a reaction but it won’t be as good. It’s really a balance.”
And even with broad-spectrum corona vaccines, the possibility remains that viruses will escape them through mutation, says Kikkert. “It’s a constant arms race. Ultimately, the trick is to choose something that makes it as difficult as possible for the virus to adapt, then it would take longer for a vaccine to become less useful.”
“A comprehensive pancorona vaccine may prove to be a utopia,” Rogier Sanders also says. “That would of course be a great pity, but above all we have to try. If it doesn’t work, then there’s nothing left to do but chop it up into smaller pieces, and make a panbetacoronavirus vaccine alongside a panalfacoronavirus vaccine, for example.”
Since we cannot predict from which corner the danger of a new vaccine-resistant variant or a new pandemic coronavirus will come, Berend Jan Bosch says it is wise to focus vaccine development on known high-risk viruses. “We now know that two SARS-like viruses have made that leap from animal to human. That’s clearly a high-risk group. But nature will always surprise us in that regard, because other coronaviruses can also just end up in humans. There are two recent examples of that. One came from pigs, a so-called porcine delta coronavirus, and the other came from dogs, a canine coronavirus. In both cases this did not cause a large-scale outbreak, but the people infected by it did have symptoms of illness. That just goes to show that a coronavirus outbreak could also come from an unexpected source.”
CORONAVIRUSES A VERY LARGE FAMILY
Coronaviruses get their name from their appearance: under the microscope, the virus particle is surrounded by a wreath of spike proteins, resembling a crown (corona).
The outward uniformity is deceptive, because genetically these rna viruses are very diverse. They are classified into four main groups designated by a Greek letter (not to be confused with the SARS-CoV-2 variants which are also given a Greek letter).
Of the corona infections in humans, two come from the alphacoronaviruses; the cold viruses 229E and NL63. The rest fall under the beta coronaviruses. Except for cold viruses OC43 and HKU1, all SARS-like viruses (sarbecoviruses) and MERS belong to this group. Gamma and delta coronaviruses frequently cause infections in birds and pigs
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