The arrival of the next pandemic is a matter of when not if.
"COVID-19 was the third major and serious coronavirus epidemic or pandemic following SARS in 2002 and MERS in 2012,” said researcher Dr. Peter Hotez, dean of Baylor College's National School of Tropical Medicine and co-director of the Texas Children's Hospital Center for Vaccine Development. “We should anticipate a fourth coronavirus outbreak within the next decade or so."
To prepare for the inevitable, we will need government-funded basic science in universities and the collaboration of drug companies experienced in vaccine research and development. A "universal" vaccine that protects against infections by existing and future variants would be a hugely important advance.
We have learned a lot about the SARS-CoV-2 virus during the more than four years since the COVID-19 plague shook our world. Because the virus replicates its RNA and mutates in every infection, its spike proteins keep changing. Thus, by the time a vaccine targeting a specific spike protein becomes available, a new variant of the virus with a new spike protein is likely to have emerged, one that might be more transmissible, cause more severe disease or be more resistant to immunity from previous infection or vaccination.
New viral variants such as the original Omicron and the many subtypes descended from it were less susceptible to the vaccines developed to protect against the original Wuhan SARS-CoV-2. Moreover, even when the vaccine and virus are a good match, protection from the vaccine wanes substantially with time.
For those reasons and because uptake of the newest round of vaccines has been anemic in the U.S., we are still experiencing more than 5,000 COVID hospitalizations per week. Fortunately, the numbers of COVID-related emergency visits, hospitalizations, deaths, and levels of SARS-CoV-2 in wastewater (an early predictor of future COVID infections) are trending downward, a cause for cautious optimism. But many new cases are still occurring, and the SARS-CoV-2 virus continues to replicate, mutate, and evolve.
Although we are far below the COVID peaks during the height of the pandemic, there are reasons for concern about the future – especially the increasing ability of successive SARS-CoV-2 variants of concern to escape immunity from both natural infection and vaccination and the risk of spillovers of various animal coronaviruses into humans. For example, a 2015 article in Nature Medicine by an international group of researchers described the peril posed by a SARS-like virus, SHC014-CoV, and concluded that there was “a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.” Other coronavirus researchers have expressed similar concerns over the past decade.
Prospects for a universal vaccine
We need to be prepared for the emergence of new SARS-CoV-2 "variants and other pandemic viruses. The key is to develop new vaccines that are as close as possible to a “universal vaccine” that would protect against multiple types of coronaviruses. Several approaches are being taken, including:
- modifying adenoviruses as a vector for vaccine antigens;
- using ferritin nanoparticles and self-amplifying RNA (which works similarly to messenger RNA (mRNA) except that it can replicate itself once inside the body's cells);
- incorporating different fragments of the SARS-CoV-2 virus' spike proteins, which the virus uses to bind to human cells and gain access to elicit a broader immune response;
- focusing on parts of the virus that have been highly conserved – that is, that do not tend to mutate – in previous variants of concern.
Caltech Professor Pamela Bjorkman and her colleagues have used the multiple-spike-proteins approach with some preliminary success. They have presented the immune system – in animal models, to this point – with fragments of the spike proteins from SARS-CoV-2 and seven other SARS-like betacoronaviruses that have been attached to a protein nanoparticle, forming a structure that induces the production of a broad spectrum of cross-reactive antibodies. Early results showed that antibodies elicited by this synthetic vaccine were able to bind not only to the eight coronaviruses whose spike proteins are represented on the nanoparticle but also to four additional coronaviruses whose spike proteins are not in the vaccine.
Another important finding was that “when vaccinated with this so-called mosaic nanoparticle, animal models were protected from an additional coronavirus, SARS-CoV, that was not one of the eight represented on the nanoparticle vaccine” (emphasis in original). That implies that the vaccine might protect against subvariants of SARS-CoV-2 that have not yet appeared.
The group reported that the vaccine appeared to protect mice and monkeys exposed to an array of coronaviruses. Professor Bjorkman hopes to have a vaccine in clinical trials by the end of this year.
U.S. Army medical researchers are also making important advances, developing a nanoparticle that elicits neutralizing antibodies against the original (Wuhan) SARS-CoV-2 virus and subsequent variants of concern, as well as against SARS-CoV, the virus that caused the SARS outbreak 20 years ago. Their vaccine-elicited immune responses that rapidly eliminated replicating virus in the upper and lower airways and lung tissue of nonhuman primates after the high-dose SARS-CoV-2 virus challenge. They have a vaccine in an early clinical trial.
A computation-based method
Yet another recent approach is being taken by a multinational group of academic and industry researchers who used a “viral-genome-informed computational method for selecting immune-optimized and structurally engineered antigens” to identify an antigen structure that elicited broad-based immune responses against different members of the large group of SARS and SARS-CoV-2-related viruses that occur in nature. They showed that “a single antigen based on the receptor binding domain of the spike protein elicits broad humoral responses against SARS-CoV-1, SARS-CoV-2, and two other viruses in mice, rabbits, and guinea pigs.” Phase 1 clinical trials are underway in England.
In a Your Local Epidemiologist column, Katelyn Jetelina, and Andrea Tamayo reported that approximately 20 next-generation universal COVID vaccines are in the early (preclinical) stages of development, and five have reached clinical trials:
Variant-proof COVID-19 vaccines that have made it to clinical trials. Figure by Your Local Epidemiologist (Katelyn Jetelina). Data from Hilda Bastian.
In addition, they list 27 clinical trials of mucosal (nasal) COVID vaccines that are in clinical trials, most of which are conducted outside the U.S. In theory, they might better prevent infection and transmission of infections because they induce antibodies at the site of most virus exposures – the nose and throat.
Another new approach: self-amplifying RNA vaccines
Another innovation in COVID vaccine development is self-amplifying RNA vaccines (samRNAs), which was the subject of an April 18 article by India-based researchers in the journal Nature Medicine. They reported:
GEMCOVAC-OM [the vaccine] was found to be safe and well tolerated and generated significant humoral as well as cellular immune responses against the B.1.1.529 [Omicron SARS-CoV-2] variant. GEMCOVAC-OM is thermostable and the first samRNA vaccine to receive an Emergency Use Authorization. Moreover, it is the only Omicron-specific vaccine that is approved in India.
In January, a different self-amplifying mRNA vaccine (ARCT-154) made by Arcturus Therapeutics and CSL received full approval as a COVID-19 booster in Japan. In the pivotal Phase 3 study, the vaccine was administered at a 5 microgram dose, which resulted in higher immune responses than a 30 microgram dose of Comirnaty, the Pfizer/BioNTech vaccine. Several other samRNA vaccine candidates are in clinical trials.
Looking forward
Substantial amounts of public and private research funding are being made available for ongoing work on such vaccines. The Coalition for Epidemic Preparedness Innovations (CEPI) has provided initial funding of around $200 million, which the NIH supplemented with $36 million. However, those expenditures will not begin to cover the costs of the clinical trials required and fall far short of the approximately $10 billion spent by the Trump Administration on Operation Warp Speed, which was instrumental in developing and distributing the first round of COVID vaccines in 2020 in record time.
Some of that slack will likely be addressed by U.S. Department of Health and Human Services funding of more than $500 million to develop next-generation COVID-19 vaccines, which is part of the government's $5 billion Project NextGen. Its areas of focus include vaccines that are easier to administer and produce longer and more robust protection, as well as the development of new technologies that will enable faster, cheaper, and more flexible production of vaccines.
Another pandemic will happen. The key question: Will we have done the extensive research necessary to limit its potentially catastrophic impact? To be prepared, we need government-funded basic science in universities and the collaboration of drug companies experienced in vaccine research and development.
Henry I. Miller, MS, MD
Henry I. Miller, MS, MD, is the Glenn Swogger Distinguished Fellow at the American Council on Science and Health. His research focuses on public policy toward science, technology, and medicine, encompassing a number of areas, including pharmaceutical development, genetic engineering, models for regulatory reform, precision medicine, and the emergence of new viral diseases. Dr. Miller served for fifteen years at the US Food and Drug Administration (FDA) in a number of posts, including as the founding director of the Office of Biotechnology.
