March 15, 2023 -- The COVID-19 vaccines were a remarkable medical accomplishment, credited with preventing more than 3 million deaths and 18 million hospitalizations in the U.S. alone in 2 years, but scientists and public health officials say future versions will have to work even better.
Current vaccines are best at preventing serious illness, hospitalizations, and death. Improved vaccines would need to up the ante and make infection and transmission far less likely.
Researchers from around the globe are also working on ways to make the vaccines easier – think pill, liquid, nasal spray, or patch – while making them less vulnerable to variants, with fewer side effects.
All of this could perhaps help many people overcome their resistance to getting vaccinated, which is plainly evident from the numbers: Worldwide about 72% of people have received at least one dose of a COVID vaccine. The number of Americans with one dose is higher at more than 81%, but just 16.3% have agreed to get a booster, according to the CDC.
The current crop of vaccines, notably mRNA, may not be enough. Anthony Fauci, MD, the former head of the National Institute of Allergy and Infectious Diseases, and former chief medical adviser to the president, recently told WebMD, "We certainly want next-generation vaccines" that are broader and more adaptable, cover multiple variants, and offer "a greater degree of duration.”
Fauci is not alone in his assessment. A lot of recent research has moved beyond the immediacy of pandemic survival to reflection and planning for better vaccines.
On Feb. 21, the University of Minnesota's Center for Infectious Disease Research and Policy released its Coronavirus Vaccines Research and Development Roadmap, a comprehensive 92-page report highlighting different paths to success and hurdles along the way. Among the approaches suggested by the team of 50 scientists who collaborated on the report:
- A step-by-step process that starts with vaccines to protect against variants of the coronavirus
- A focus on vaccines that could protect against multiple coronaviruses, including those that might spill over from animals to humans
Right now, research is taking multiple approaches.
- Targeting internal parts of the virus that don't change
- Updating vaccines based on expected future variants
- Changing routes of administration
- Modulating the preexisting antibody response to the original vaccine to allow booster shots to work better
As presented below, researchers around the globe are fast at work to put these goals into practice.
Ultimate Goal: Pan-Variant Vaccine?
The ultimate goal is to develop vaccines that offer such broad protection they would be "future-proof," as the Coalition for Epidemic Preparedness Innovations, a foundation in Oslo, Norway, that funds research, calls it.
Such a vaccine or vaccines would be able to target existing coronaviruses, variants that evolve, and coronaviruses that emerge well into the future.
Current vaccines target the coronavirus' infamous spike protein, which allows the virus to penetrate host cells, but is known to mutate. To make vaccines ever-ready for the next variants, some researchers are instead focusing on parts of the coronavirus that stay the same even as new variants emerge — and those “conserved” parts are still being discovered.
Most researchers, according to the Norwegian researchers, are focused now on a subset of coronaviruses known as the Betacoronavirus group, deemed most worrisome. The group includes SARS-CoV-2 that causes COVID-19, but also the coronaviruses that cause severe acute respiratory syndrome, or SARS, and Middle East respiratory syndrome, or MERS, as well as coronaviruses that cause the common cold.
Researchers are working on an mRNA vaccine that targets elements of the viral structure common to all known common betacoronaviruses. These elements are presumed to be critical to the virus' survival and ability to replicate, so probably less likely to change.
In support of this concept, CEPI has given money to a biotech spinoff from the University of Cambridge called DIOSynVax, a U.K.-based company that analyzes the structure and evolution of viruses and then custom designs platforms of antigens (the weakened or inactivated form of the virus in the vaccine that triggers the antibody response) that will give broad protection.
Another broad-protection type of vaccine, called a mosaic nanoparticle vaccine, includes pieces of the spike protein from SARS-CoV-2 as well as from other coronaviruses, with the goal of providing protection against many coronaviruses at once. One such vaccine currently being studied in animals at the California Institute of Technology in Pasadena includes pieces of the spike protein from SARS-CoV-2 and seven other coronaviruses.
The fragments of the viruses that the researchers picked, called receptor-binding-domains or RBDs, are crucial for coronaviruses to be able to enter human cells. When human antibodies neutralize coronaviruses, they do so by focusing on these domains of the virus. The vaccine as tested protected animals from all the strains evaluated, plus an additional one that was not one of the eight represented on the vaccine, researchers reported.
Tried and True
While mRNA vaccines get most of the attention in combating COVID-19, developers of more traditional vaccine platforms are also focused on keeping ahead of future variants.
One company that has an emergency authorization from the FDA for a COVID-19 vaccine, Novavax, is using what's known as a protein subunit technology, the same technology used in the hepatitis B vaccine and modern whooping cough vaccines. After the vaccines are injected, nearby cells pick up the proteins. The immune system recognizes them as invaders and another ingredient in the vaccine, called the adjuvant, helps the immune system produce antibodies.
At a January meeting of the FDA's Vaccine and Related Biological Products Advisory Committee meeting, Novavax leaders reported that its vaccine composition update is expected to work against future variants – but typical of this type of vaccine, more time is needed to ramp up production than some of the newer vaccine platforms.
Other Routes of Administration
When injected in muscle, COVID-19 vaccines move throughout the body quickly. But researchers are also investigating other routes of administration.
Nasal COVID-19 vaccines and inhaled vaccines can produce a strong mucosal immune response in the respiratory tract, where the virus first infects people, as well as body-wide responses. Experts say that could mean these vaccines are better at stopping the virus at a main entry point, the nose.
A needle-free vaccine under study is deposited to the immune cells right beneath the skin's surface. A pill aimed at preventing COVID-19 may also work to trigger multiple responses. A drinkable vaccine aims to train the lymphatic system to recognize and respond to the virus.
Bharat Biotech International Limited launched a nasal vaccine, called iNCOVACC, in January in India. It can be taken as both a primary vaccine and a booster. The vaccine is based on technology developed at Washington University in St. Louis and licensed to Bharat.
In a clinical trial, nearly 3,000 adults received two doses of the nasal vaccine while 162 in a comparison group received two doses of an injected COVID vaccine. The intranasal vaccine was well tolerated and gave “superior” immune responses compared to the shot, researchers reported.
Other nasal vaccine research, funded by the the National Institutes of Health, has shown promising results in animal studies.
Needle phobias make it difficult for some to get injections. According to the CDC, as many as 2 out of 3 children and 1 out of 4 adults have “strong fears” about needles, and 1 in 10 might put off the COVID-19 vaccine because of that fear.
Vaxxas, headquartered in Cambridge, MA, is developing a needle-free vaccine patch, with funding from CEPI. The patch will not only help those not fond of needles but also end the need for frozen storage of vaccines, says David L. Hoey, president and CEO of Vaxxas.
The 3/8 inch patch has tiny projections, a fraction of a millimeter long, with vaccine on their tips, Hoey says. It is applied to the skin for about 10 seconds and the drug is deposited to the immune cells directly beneath the surface of the skin. You don't notice the projections going in, he says.
“The immune response happens much faster [than with injected vaccines] so you get protected faster,” Hoey says, adding that the patch has potential to be self-administered, eliminating the need for health care providers to do it.
Pop a Pill
A vaccine pill under study by Vaxart Inc., increased antibody response to the virus in a phase II study that enrolled healthy adults, including some who had not yet gotten vaccinated against COVID-19.
Next, according to the company, it will launch a study that gives people the vaccine pill and then exposes them to COVID in a controlled setting – a controversial method. That study is expected to begin in late 2023 or early 2024.
Also under study is a drinkable vaccine currently just labeled QYNDR, which trains the lymphatic system – which makes, stores, and distributes white blood cells that defend the body against infection -- to recognize and respond to COVID-19 strains, according to U.S. Specialty Formulations, which is collaborating with Syneos Health.
Along with its self-administered "swish and swallow" procedure, as the company calls it, the vaccine also does not need to be refrigerated.
Phase I research, not yet peer-reviewed, produced promising results, the company says. They are seeking co-funding for larger trials.
CanSino Biologics has an inhaled vaccine, first approved as a booster vaccine in China in 2022. It works differently from a nasal vaccine because users take a puff of air from a nebulizer, then inhale it by mouth. But similar to nasal vaccines, it can also induce "mucosal immunity," according to the company.
Other research is focused on how the antibodies generated by the original COVID-19 vaccines may limit the effectiveness of the subsequent booster shots, and what to do about it.
“What happens is, those antibodies play a critical role in protecting you against the virus,” says Pablo Penaloza-MacMaster, PhD, assistant professor of microbiology and immunology at Northwestern University's Feinberg School of Medicine in Chicago, “but those antibodies do the same thing to the vaccine.”
His team's studies have found that antibodies generated by prior vaccines speed up the clearance of the vaccine from the body, making less vaccine available to trigger new immune responses after the booster.
His team is testing how to block that effect to improve how well the boosters work. One way may be to give patients a drug that reduces antibody activity for just for a few hours, Penaloza-MacMaster says, to allow the vaccine to work better. The researchers are investigating whether a drug could be mixed with the vaccine or co-administered along with the vaccine.
Other researchers are focused on the body's T-cell responses to COVID-19, which researchers say have been underestimated so far. T cells kill other cells infected by the SARS-CoV-2 virus. Researchers have discovered that T cells tend to recognize parts of SARS-CoV-2 that don't mutate quickly. Researchers are studying experimental vaccines that include compounds to trigger a strong T-cell response.
Fewer Side Effects
Tiba Biotech in Cambridge, MA, is developing a different mRNA platform designed to cause less inflammation after vaccination, potentially reducing fevers, sore arms, and other side effects.
Currently, mRNA (which instructs cells to make specific proteins and trigger the immune system to make antibodies against the virus) is encased in tiny balls of fat called lipid nanoparticles to protect it from degradation and deliver it safely.
“We are trying to replace parts of that lipid shell with this alternative molecule,” says Jasdave Chahal, PhD, chief scientist and co-founder of Tiba Biotech. The company has a contract with CEPI to develop this type of vaccine delivery platform initially to test against Japanese encephalitis virus, but it is expected to have applications for SARS-CoV-2 and several other viruses.
Research on new or improved vaccines varies in progress, but in general the development of these are “a long haul,” says Melanie Saville, executive director of vaccine research and development at CEPI. The aim for research they fund, she says, is to have proof of concept studies for a broadly protective, variant-proof vaccine in 2023, with another year or 2 required to obtain licensing for use.
If all goes well, experts hope that variant chasing may be history by 2024 or 2025.
David L. Hoey, president and CEO of Vaxxas, Cambridge, MA, and Brisbane, Australia.
Pablo Penaloza-MacMaster, PhD, assistant professor of microbiology and immunology, Feinberg School of Medicine, Northwestern University, Chicago.
Jasdave Chahal, PhD, co-founder and chief scientist, Tiba Biotech, Cambridge, MA, and Brisbane, Australia.
Vaxart news release: “Vaxart Announced Positive Top-line Phase II clinical Study Data Demonstrating Safaety and Immunogenicity of Its Wuhan S-Only COVID-19 Pill Vaccine Candidate.”
Mark Herr, spokesperson, Vaxart Inc.
The Commonwealth Fund: “Two Years of U.S. COVID-19 Vaccines Have Prevented Millions of Hospitalizations and Deaths.”
The Lancet Infectious Diseases: “Global impact of the first year of COVID-19 vaccination: a mathematical modelling study.”
CDC: COVID Data Tracker, “Needle Fears and Phobias—Find Ways to Manage.”
U.S. Specialty Formulations news release: “Research Demonstrates Benefits of Oral COVID-19 Vaccine.”
CanSino Biologics Inc. statement: “Inside Information.”
Coalition for Epidemic Preparedness Innovations: Email statement; News releases: “The Race to Future-Proof Coronavirus Vaccines;.” “Coming in from the cold: needle-free patch technology for mRNA vaccines aims to end need for frozen storage and improve access.”
Executive Office of the President: “Statement of Administration Policy.”
Science: “Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models.”
Caltech news release: “Nanoparticle Vaccine Protects Against a Spectrum of COVID-19-causing Variants and Related Viruses.”
U.S. Government Accountability Office. “Operation Warp Speed.”
Bharat Biotech International Limited news release: “Bharat biotech launches iNCOVACC: World’s 1st intranasal COVID vaccine for Primary series and Heterologous booster.”
The Lancet preprints: “Immunogenicity and Tolerability of BBV154 (iNCOVACC®), an Intranasal SARS-CoV-2 Vaccine, Compared with Intramuscular Covaxin® in Healthy Adults: A Randomised, Open-Label, Phase 3 Clinical Trial.”
Cell: “Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in monkeys.”
National Institute of Allergy and Infectious Diseases news release: “NIAID Issues Further Awards to Support Pan-Coronavirus Vaccine Development.”
CEPI news release: “CEPI and DIOSynVax partner in quest to develop broadly protective Betacoronavirus vaccine.”
CDC: “Understanding How COVID-19 Vaccines Work.”
Nature Immunology: “The T-cell immune response against SARS-CoV-2.”
National Institutes of Health: “T cells protect against COVID-19 in absence of antibody response.”
PNAS: “Vaccine-induced systemic and mucosal T cell immunity to SARS-CoV-2 viral variants.”
Cell Reports: “Pre-existing immunity modulates responses to mRNA boosters.”
University of Minnesota Center for Infectious Disease Research and Policy: “Coronavirus Vaccines R&D Roadmap.”
NIH news release: “2NIAID Studies Highlight COVID-10 Natal Vaccine Potential.”
U.S. Specialty Formulations news release: “Research demonstrates benefits of oral COVID-19 vaccine.”