Is a Universal Coronavirus Vaccine a Possibility?

[This text has been published in Spanish in EFEsalud]

The COVID-19 pandemic has taught us a great deal about coronaviruses, the family of pathogens widespread in nature that recently triggered one of the most dramatic health crises in modern history. But SARS-CoV-2 is not the only coronavirus that causes disease in humans. A few years ago, several Asian countries experienced major epidemics caused by two other coronaviruses—SARS-CoV (2003) and MERS-CoV (2012)—both of which were associated with severe respiratory syndromes but did not spread worldwide.

Here in Europe, we have always lived with other, less threatening endemic coronaviruses: the seasonal pathogens that cause the common cold (HCoV OC43, HKU1, 229E, NL63). As well as having these more or less dangerous first cousins, SARS-CoV-2 itself is capable of evolving when its genome mutates and gives rise to variants that are more transmissible and better at evading the host’s immune response. Mutations have led to the emergence of numerous variants and strains, including Alpha, Beta, Gamma and Delta as well as, more recently, Omicron. And these variants have caused successive waves of infection around the world and jeopardised the effectiveness of vaccines.

Photo: Samuel F. Johanns/Pixabay

So we know that coronaviruses are a very large and highly adaptive family of viruses capable of jumping from animals to humans, causing what we call zoonoses. For many years, both One Health specialists and experts studying microbes with the potential to generate epidemics have been investigating microbes that have already caused epidemic outbreaks, including flaviviruses and the influenza viruses. Coronaviruses were also among the usual suspects.

Coronaviruses are a very large and highly adaptive family of viruses capable of jumping from animals to humans, causing what we call zoonoses.

Fortunately, vaccines developed in the record time of one year played a key role in curbing the mortality and severe morbidity of disease during the initial waves of the COVID-19 pandemic. Now vaccines could also become essential tools in the prevention of emerging coronaviruses. A hot topic in the debate on preparedness for the next pandemic is whether it is possible to create more universal vaccines, that is, vaccines that offer protection not only against SARS-CoV-2 but also against all coronaviruses (a pan-coronavirus vaccine), including the novel virus that may cause the next Disease X.

The Importance of Cross-Immunity

Cross-immunity has been an important topic in the debate since the start of the COVID pandemic. Given the similarities between different coronaviruses, is it possible that pre-existing antibodies to other endemic coronaviruses may provide some level of protection in certain groups of individuals, for example children, who are more exposed to Human Coronavirus (HcoV) colds? In some ISGlobal studies, we found associations between the presence of higher levels of antibodies against HCoV and resistence to infection with and/or disease caused by SARS-CoV-2. Furthermore, it was prior knowledge regarding the SARS-CoV spike protein and its use in the clinical development of a vaccine that facilitated the rapid development of the first generations of COVID-19 vaccines because of the similarities in protein sequence between coronaviruses.

Is it possible that pre-existing antibodies to other endemic coronaviruses may provide some level of protection in certain groups of individuals, for example children, who are more exposed to Human Coronavirus (HcoV) colds? .

The evidence of cross-immunity supports the hypothesis that it would be possible to achieve the ambitious goal of creating a pan-coronavirus vaccine. To do this, we would need to identify the epitopes or antigenic determinants (the portions of the virus that stimulate an immune response) which are sufficiently conserved to transcend the differences between virus types and their variants. Another point in favour of such a vaccine, particularly with respect to the cellular immune response, is that there is evidence of a significant degree of cross-immunity between different coronaviruses. Unfortunately, the task also presents major challenges given the evidence that immunity can also be species-specific and variant-specific, particularly in the case of the neutralizing antibody response.

Universal vs Genera-Specific Coronavirus Vaccines

In light of all of the above considerations, the scientific community believes that a universal vaccine effective against all coronaviruses may not be a realistic goal, but that a more achievable objective could be to develop vaccines targeting groups of more closely related coronaviruses, in which cross-immunity might play a major role. In order to design effective strategies, we must first identify the similarities and differences between the various types of coronaviruses and then choose the most appropriate target antigens. For example, depending on their genetic makeup, human coronaviruses are classified into genera, such as the alpha-coronaviruses and the beta-coronaviruses (to which SARS-CoV-2 belongs). A vaccine might be effective within a single genus but not for two genera.

The scientific community believes that a universal vaccine effective against all coronaviruses may not be a realistic goal, but that a more achievable objective could be to develop vaccines targeting groups of more closely related coronaviruses .

Most current research is targeting sarbecoviruses (the subgenus that includes all SARS-like viruses) or beta-coronaviruses—the largest branch of the family tree (which includes MERS and some seasonal common cold coronaviruses). To develop pan-sarbecovirus vaccines we need more advanced vaccine formulations capable of inducing broader and more powerful antibody and T-cell responses in order to minimise evasion of the immune responses targeting the virus fragments that differ most between the species. There are currently ten candidate vaccines in clinical or preclinical stages that have been designed to offer broad protection. The technologies used include formulations of second-generation messenger RNA (mRNA), viral-like particles (VLP), and mosaic nanoparticles. The aim is to induce more robust immune responses against different variants, antigens and types of viruses.

Photo: Governor Tom Wolf/Flickr

These approaches should not be confused with two other concepts that have been discussed in the debate on pan-coronavirus vaccines and elsewhere: the non-specific effects of vaccines, and the cross-reactivity of the immune response between different pathogens. In the case of non-specific effects, for example, a growing number of studies show that certain vaccines, such as the Bacillus Calmette–Guérin (BCG) vaccine for tuberculosis, can provide non-specific protection against other, unrelated diseases. The mechanisms for this effect include a boost to the innate immune response and a process called “trained immunity” mediated by epigenetic modifications. During the pandemic, some research groups postulated that the BCG vaccine might offer some protection against SARS-CoV-2 and tested this hypothesis. With respect to cross-reactivity between pathogens, some studies have reported certain similarities in antigen sequences between SARS-CoV-2 antigens and other pathogens (including bacteria). The implication is that existing vaccines could have an unforeseen protective effect owing to the presence of shared epitopes and cross-reactivity between different microbes. More research is needed to confirm the extent and impact of this, as yet unexplored, phenomenon.

There are currently ten candidate vaccines in clinical or preclinical stages that have been designed to offer broad protection.

We are currently witnessing a substantial increase in infections and reinfections by the highly transmissible Omicron 4 and 5 variants, which are capable of evading the immune response even among vaccinated individuals. In light of this and the risk of an increase in severe and/or persistent cases of COVID-19 and of a repeat of the recent health care crisis, there is every reason to accelerate the development—just as aggressively as in 2020—of a new generation of nasal vaccines aimed at more effectively preventing infections (through mucosal immunity) and of new pan-coronavirus vaccines that can provide sufficiently broad cross-immunity against existing variants and novel X variants that may appear in the coming months.