Variant-resistant vaccines – invest now for the next pandemic

The rapid development and delivery of highly effective COVID-19 vaccines less than a year after the onset of the disease is a great success story. This was partly possible due to certain properties of the coronavirus SARS-CoV-2 that favor the design of vaccines – in particular the vein protein on the surface of the virus. It requires the body to make protective neutralizing antibodies (proteins that bind to viruses and prevent them from infecting human cells). This is likely responsible for the efficacy of current COVID-19 vaccines.

The next pathogen that emerges is perhaps less accommodating. It can take much longer to make a vaccine. Even SARS-CoV-2 may become more problematic for vaccines due to the emergence of new variants. We call for an alternative approach to pandemic preparedness.

A special class of protective antibodies called broad neutralizing antibodies (see ‘Pan virus vaccines’) work against many different strains of related viruses – for example HIV, influenza or coronavirus. Such antibodies can be used as first-class drugs to prevent or treat viruses in a particular family, including new generations or strains that have not yet emerged. More importantly, it can be used to design vaccines against many members of a particular family of viruses.

Such pan-virus vaccines can be pre-made and used before the next emerging infection becomes a pandemic. We call for an investment in basic research leading to the storage of broad effective vaccines. As we have seen with the flu, one virus strain can cause more deaths than a world war and lead to trillions of dollars in economic damage. Global governments that together spend US $ 2 trillion a year on defense can surely find a few hundred million dollars to stop the next pandemic?

Evasion tactics

Why has vaccine design for SARS-CoV-2 been relatively easy (so far, at least)? Infection begins when the vein protein attaches to the surface of a receptor in human cells. The virus injects its genetic material into the cell and takes it over to produce many copies of itself, eventually leading to disease. Neutralizing antibodies stop this viral entry and prevent infection. On SARS-CoV-2, the attachment site is a large, open protein surface on which antibodies adhere easily. Thus, it is relatively easy for a vaccine to stimulate protective neutralizing antibodies.

In evolutionary terms, SARS-CoV-2 is an ‘escape light’ pathogen. It does not need to acquire a weapon of molecular properties to neutralize immune responses in general and antibodies in particular. This is because it is currently transmitted from one person to another before immune responses develop – and in many cases before disease symptoms are noticed.

Other pathogens are ‘evasive’. The extreme example is HIV. It coexists with human immune systems, possibly for years, before being transmitted. It has therefore developed many ways to thwart our defense, including extended series variation. This is known as immune flight. Even in one infected person, there can be 100,000 different HIV strains, any of which can be transmitted.

A vaccine that tries to block this transmission should generally neutralize antibodies that are effective against most HIV strains. It is encouraging that many such antibodies have been identified in infected people¹. This suggests that an HIV vaccine is in principle possible if researchers can learn how to induce antibodies through immunization. Intensive research over the past ten years or so has yielded promising approaches, but a vaccine is probably another decade away.

The emergence of another pathogen with the evasive ability of HIV may be the worst case for a pandemic.

Influenza virus is another evasive pathogen. Its great variability is a challenge for vaccine design. The current temporary solution is to try to predict which strains will dominate in the next flu season and prepare a vaccine accordingly. Researchers have been looking for a long-term solution – a universal flu vaccine – that would protect against all flu strains, inspired by the discovery of antibodies against many or most strains.

Similar to SARS-CoV-2, influenza has protein proteins on its surface. Broadly neutralizing antibodies have been identified that target the head (top) and stem of hemagglutinin, one of the ear proteins. Antibodies against the stem are very broad, but not as powerful; clinical studies using it to treat flu have been disappointing² (see also go.nature.com/3phhtcm). Antibodies to the head are less broad but more powerful³.

As for the potential of pandemic, flu virus tick all the boxes. It is a respiratory virus, is easily transmitted between humans and has animal reservoirs. Indeed, many researchers consider influenza to be the greatest threat of the pandemic, and fear a recurrence of the 1918 pandemic, which killed more than 50 million people worldwide with a death toll of about 2.5%. To date, COVID-19 has killed approximately 2.1% of the more than 100 million people confirmed to be infected worldwide, and approximately 10% of infected people have 6 months or more of health effects.

Clearly, a universal flu vaccine would be the ideal countermeasure. A more realistic approach might be to design multiple vaccination candidates based on potent antibodies against a limited number of influenza viruses, perhaps organized by influenza subtypes. The supply of specific flu vaccines and the collection of antibodies can then be ensured. The vaccines can be created in the formats used for those against SARS-CoV-2: messenger RNA and viral vectors such as adenovirus, both of which are susceptible to rapid scaling and deployment.

Priority viruses

Several notable variants of SARS-CoV-2 have emerged in the past few months, including B.1.1.7, B1.351 (also known as 501Y.V2) and P.1. It was first identified in the United Kingdom, South Africa and Brazil, respectively, and each variant has many mutations in the important protein. Laboratory studies indicate the possibility of immune flight^4,5,6,7 with at least one of these variants. There is also now initial evidence from two clinical trials against vaccine indicating reduced efficacy in the prevention of mild to moderate COVID-19 in individuals infected with the B.1.351 variant (see go.nature.com/2ydkrxs and go .nature.com/2musicv), although the candidates for vaccinations appear to have serious illnesses. Over time, unimpeded distribution and accelerated evolution in immune-driven hosts can cause enough mutation to significantly, or even completely, reduce the effectiveness of current vaccines. We then need vaccines that cause antibodies that can neutralize the variants of SARS-CoV-2, as well as the original virus.

Many antibodies that generally neutralize, effective against both SARS-CoV (the virus that causes severe acute respiratory syndrome, SARS) and SARS-CoV-2, have been isolated from donors infected with one of the two individual viruses alone.^8,9,10. It can form the basis of vaccines designed to contain SARS-related coronaviruses (sarbecoviruses) in general, including possible coronaviruses that have not yet emerged. Broadly neutralizing antibodies have also been isolated that are effective against a wider range of beta-coronaviruses (the genus that Sarbecovirus lineage), including MERS virus (MERS) and seasonal coronaviruses¹¹. This in turn could sow projects to design broad vaccines.

There are viruses against which it is relatively easy to cause protective neutralizing antibodies by vaccination. Even here, the existence of subtypes and the possibility of others emerging suggest that the discovery of antibodies may in general be valuable for the design of vaccines to protect against existing and future viruses. For example, there are six subtypes of Ebola virus; two have emerged over the past 15 years. There are broad neutralizing antibodies that strongly counteract multiple subtypes¹².

Several more viruses have been identified as potential pandemic threats by the Oslo-based Coalition for Epidemic Preparedness Innovations (CEPI). In addition to Ebola, CEPI cites MERS, Lassa, Nipah, Rift Valley fever and chikungunya viruses as priorities for vaccine development. It should be at the forefront of the search for antibodies and rational vaccine design.

If not now, when?

What are the fiercest critics of our proposals? They point to the problems of isolating neutralizing antibodies with sufficient strength and width to be effective. They take note of the complexity of rational vaccine design. They emphasize concern about evolution of pathogen and resistance to antibodies. They ask why this approach has not yet been widely applied.

It can be difficult to generate very broad, very powerful neutralizing antibodies. But research to find and improve the best antibodies has been very successful over the past few years. It may not always be possible to obtain the ideal answers in a whole family of viruses. But compromises can be made, and methods of delivering antibodies (for example, two or three) and vaccinations become feasible.

There are already bags of promise. Rational design has yielded a favorable vaccine, currently in phase III trials, against respiratory synthesis virus – the cause of serious, sometimes fatal diseases in young people. This virus has defied conventional vaccine development efforts for more than 50 years. Rational design approaches are underway for important pathogens such as HIV, influenza and malaria, although not on the scale we propose here.

It is important that early inclusion or eradication of an emerging virus significantly reduces the likelihood that it will develop resistance to antibodies and vaccines.

Costs and investors

Unlike a reactive program that takes effect when a new pathogen appears, we propose goals that can now be described and projects that can begin on a large scale immediately. Thanks to work already done on other viruses, especially HIV and influenza, the approaches are understood and the infrastructure is in place. Investments made so far in basic science – including virology, genomics, immunology and structural biology – have provided us with a unique opportunity to advance further SARS-CoV-2 evolution and put us in a powerful position for new viral pathogenic.

The investment per virus from trials to Phase I trials is likely to be between $ 100 and $ 200 million over several years. We anticipate that these costs will be borne by public-private partnerships between governments, philanthropy and industry. Organizations such as CEPI, the COVAX facility and GAVI, the vaccine alliance can help bring together the expertise and start negotiations to deliver the types of vaccine we propose.

We will break out in the future, and we will probably see further epidemics. We need to stop it becoming a pandemic.