Doubts about a new dose in the fall: does it make sense to vaccinate against last year's omicron variant?

"We can make a new vaccine in six weeks," BioNTech CEO Ugur Sahin said in December 2020 with the arrival of the alpha variant. It was a vague statement open to interpretation: Even if the upgrade was not technically complicated, repeating clinical trials—even on a small scale—changing mass production, and distributing new doses would not be as quick or easy. More than two years after those words and almost six months after South Africa introduced omicron to the world, the new vaccines have still not arrived. When they do this fall, they will be matched against a 2019 variant and a 2021 variant. Will this be a problem?

So far, attempts to adapt mRNA vaccines against the new variants have been up in the air. For example, Moderna even shared results of an update against beta, while in the summer of 2021 Pfizer announced a clinical trial with an adapted booster dose against delta that was never heard from again, despite the fact that the company claimed to have manufactured the first batch.

Most of the researchers consulted to date, in this article and in previous ones, agree on two things. In the first place, that until now it has not been urgent to update the vaccines because they have maintained their protection against serious illnesses and deaths during the pressing vaccination campaigns of 2021. Second, that in this fall prior to 2023 it would not be a bad idea to have updated doses now that the urgency of the previous phases has been left behind.

"Autumn would be a very appropriate time to be able to use them," the president of the Spanish Immunology Society, Marcos López Hoyos, told This would allow preparation for the inevitable wave of next winter. Various actors seem to think the same: the EMA has advanced its intention to authorize booster doses in September. Both the Minister of Health, Carolina Darias, and the Madrid Minister of Health, Enrique Ruiz Escudero, have pointed to autumn as the time when the fourth doses will begin.

The manufacturers of mRNA vaccines have marked the same date on the calendar, with nuances. Moderna has warned that if the FDA chooses a new variant at its meeting in late June, "no manufacturer will be able to be ready by August." The reason: that tens of millions of doses must be produced before September.

These new doses would be bivalent, that is, they would combine vaccines against two variants. On the one hand, the original variant —which virologists call Wuhan-Hu-1—; and on the other, the original omicron, BA.1. This means that the vaccines would be directed against a variant of 2019 and another of 2021.

BA.1 is already in retirement and has been replaced by its sisters BA.2, BA.4 and BA.5. Although there are doubts about whether we are not zooming in too much on the SARS-CoV-2 genome —there is also BA.2.12.1—, the truth is that we do not know how the new vaccine will work against the hypothetical variant that dominates in five months. .

Is this bivalent vaccine the best option? "It is better than repeating only with the [variante] original," explains López Hoyos. "By joining two variants, you combine a series of different mutations and increase the response spectrum, which is what it is all about. Clearly you're not going to get ahead of the variant six months from now, but you get a strong, broad-spectrum immune response."

The virologist at the Carlos III Health Institute María Iglesias thinks the same: "We don't know very well what is going to circulate from here to nothing because new variants are constantly appearing, and it was very necessary to update rather than continue vaccinating with the original variant."

Iglesias sees it as logical that the ómicron BA.1 has been chosen, although right now its circulation is very minority. "It shares 16 changes with BA.2 that are in very relevant areas and antibody binding sites, so I think it will confer protection perfectly against the omicron variants that are out there right now." He clarifies that it is a speculation based on the mutations of this family of SARS-CoV-2: "Obviously the protection is not going to be total and perfect because they have different spicules that in some omicrons can be enough".

"We cannot make the mistake of wanting to vaccinate against the latest subvariant circulating because the development of vaccines is far behind the evolution of the virus," warns the immunologist at the Hospital Clínico Universitario de Santiago José Gómez Rial. "The important thing now is to cover that qualitative leap that omicron has generated with respect to previous variants." In other words: "Do not vaccinate with the last identified omicron subvariant, but with an updated vaccine against omicron in general."

Iglesias does wonder why the update includes the original 2019 coronavirus again, which does not even have the famous D614G mutation, instead of adding a more recent variant of the B.1 family, which does.

Gómez Rial also has doubts about the chosen bivalent option: "I don't know what interest it has to incorporate a variant that no longer circulates and against which a large percentage of the world population is vaccinated and has an immunological memory." He does believe that, before opting for a single booster dose of omicron, it would be better to repeat a strategy with two or three doses.

Pharmaceutical expert in drug management and access Belén Tarrafeta does not believe that a monovalent vaccine against omicron will arrive immediately: "Pfizer and Moderna do not have a clear incentive to invest massively, change the production chain and do something different without the approval of The OMS".

Tarrafeta regrets that in the balance between commercial interest and global health "there is no orchestra director." He points to four players in the fourth dose debate: industry, the WHO, regulatory agencies, and governments and purchasing mechanisms.

For companies like Pfizer and Moderna "the approval process [de las nuevas dosis] it will be simpler, but the race is no longer to get the first vaccine but to achieve one that supposes an obvious advantage over the existing ones and those of other competitors," explains Tarrafeta. He mentions alternatives, such as nasal vaccines, which are in phases advanced and could give better results when it comes to reducing transmission.

On the other hand, the WHO seeks to guide the composition of the annual COVID-19 vaccines as it already does with the flu. "In the flu model, each year it is decided what components the new vaccine should have depending on the mutations observed in the past season, and then the industry begins manufacturing."

That process takes about six months in the case of the flu and each year it can favor more or less different companies because the technologies are different. "With the flu there is a lot of experience on how the virus mutates, but with SARS-CoV-2 things are more uncertain. The WHO needs more data to be able to guide the composition of the new vaccine, which, at the moment, comes from the industry", explains Tarrafeta. To complicate the task even more, the surveillance system to predict new mutations is still not very developed and it is not even clear whether the coronavirus will be seasonal.

As for the regulatory agencies such as the FDA and the EMA, Tarrafeta assures that "they will facilitate as much as possible" the approval of the new doses, but that "perhaps they will not be in the business of making emergency authorizations when the vaccines that we already have prevent deaths and hospitalizations". Governments and joint purchasing mechanisms, which are the customers, will guide future investment and vaccine availability with their decisions, but he fears they "encourage the status quo that disproportionately favors Pfizer and leaves little room for other vaccines."

The COVID-19 pandemic has entered a new phase and, with it, your vaccines. With the majority of the population protected and still many uncertainties about the behavior of the virus in the long term, a game of mouse and cat begins, not very different from that observed with the flu every year. On one side, a SARS-CoV-2 that has not yet lost the ability to surprise. On the other hand, researchers and experts trust that the adapted doses against ómicron will overcome any ace that the virus has up its sleeve.

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