What will the second generation of COVID-19 vaccines look like?

The incredible speed with which COVID-19 vaccines were developed, produced and rolled out brought a sense of relief across the world at the beginning of 2021. Clinical trials had shown that many vaccines were safe and effective against SARS-CoV-2 beyond any expectation. The whole world hoped that the pandemic would be brought under control.

“The development of these vaccines has been a huge success,” says Associate Professor Paul Griffin, an infectious diseases physician and microbiologist at the University of Queensland and director of Infectious Diseases at Mater Research.

“We were hoping for a vaccine that had an efficacy of greater than 50%, or 60%. And we’ve exceeded that by a very big margin.”

But with the emergence of first the Delta variant and later Omicron, it became apparent that the pandemic is far from being close to an end.

“We do need some additional properties,” Griffin says. “The second-generation vaccines will hopefully provide some of those properties we haven’t yet achieved with current vaccines.”

The need for second-generation vaccines

The vaccines rollout had an enormous impact on reducing hospitalisations and deaths, but very early it became apparent that eradication of SARS-CoV-2 was not on the cards, says Griffin.

“The efficacy of these vaccines gives us the main tools to get exceptional control [of the pandemic] and minimise the impact of this virus,” he says. “But given that the reduction in transmission is still relatively modest, eradication cannot be achieved with these vaccines.”

Second-generation vaccines that block transmission to a much higher degree than current ones could change the trajectory of the pandemic.

With the emergence of first the Delta variant and later Omicron, it became apparent that the pandemic is far from being close to an end.

Another significant issue with current COVID-19 vaccines is their short-lived immunity against infection. Despite vaccines still offering good protection against severe disease and death months after administration, waning antibodies has seen many vaccinated people to catch “breakthrough” infections.

Dr Vinod Balasubramaniam, a molecular virologist at Monash University Malaysia, says the first COVID-19 vaccines did a great job protecting us from becoming severely ill. But no one knew how long this protection would last or how well vaccines would work against new variants.

“We need new vaccines that protect against new variants because we can’t keep on boosting,” he says. “It’s not sustainable.”

Balasubramaniam says vaccine developers should focus their efforts on universal coronavirus vaccines because Omicron won’t be the last variant we will have to face, nor will SARS-CoV-2 be the last coronavirus to spill from animals to humans. “This pandemic might end, but the coronaviruses won’t die off. Other pandemics are waiting to happen.”

It’s become clear that inequitable distribution of vaccines across the world has highly contributed to the emergence of new variants. “When the vaccines came out, almost three-quarters of the doses were purchased by the rich countries like the US and Europe,” says Balasubramaniam. “The majority of the variants of concern come from those countries lagging behind [with vaccination].”

“Because Africa is not getting vaccines, we’re getting all kinds of variants from Africa. But this is not a country’s problem. It’s a global problem.”

Addressing manufacturing, storage and transportation hurdles can help solve vaccine inequity.

Easier-to-administer vaccines can also improve accessibility. Vaccines that don’t require a needle and a syringe, and use cutaneous, intranasal or oral administration instead, can be easier to make, store, transport and administer, says Balasubramaniam. Moving away from the needle could also encourage needle-phobic people to receive their doses.

There are currently several clinical trials on COVID-19 vaccines that use delivery methods other than subcutaneous injection. But Griffin says it may be more challenging to achieve high immunity levels with alternative administration methods.

Protein-based vaccines

All COVID-19 vaccines teach the immune system to recognise the virus and prepare the body to fight it off.

Unlike the three vaccines used in Australia – AstraZeneca’s viral vector vaccine, and Pfizer and Moderna’s mRNA vaccines, which provide the body with instructions on how to produce the spike protein – protein-based vaccines deliver the spike protein to the body directly.

The technology has been around for 40 years and used for the recombinant hepatitis B vaccine. 

Protein subunit vaccines have an advantage over mRNA vaccines. They can be readily produced using a well-established recombinant DNA technology that is relatively inexpensive and reasonably easy to scale up.

Production facilities for protein-based vaccines are more widely available across the world, including in low-income countries, Balasubramaniam says.

Also, protein-based vaccines have higher thermal stability, which means they can be stored for months in standard refrigerators and are easier to transport. In contrast, mRNA vaccines require very low temperatures, making storage and transport more complex and costly.

The Novavax COVID-19 vaccine (Nuvaxovid) is a protein subunit vaccine already available for use in 170 countries. It was recently approved in Australia after clinical trials demonstrated an efficacy rate above 90% and a favourable safety profile.

Protein-based vaccines have higher thermal stability, which means they can be stored for months in standard refrigerators and are easier to transport.

The vaccine started its clinical trial journey in Australia. Following promising preliminary results, it was then studied in larger trials around the world, says Griffin, who was the Principal Investigator of the Australian trials.

The novelty in the Novavax vaccine is a potent adjuvant called Matrix-M that comes from the inner bark of the Chilean soapbark tree, Quillaja saponaria, and helps create a more robust immune response to the vaccine.

The American biotechnology company based in Gaithersburg, Maryland, first used the adjuvant in an influenza vaccine. The flu vaccine yielded a more robust antibody response than existing influenza shots in a Phase III trial and provided cross-protection against multiple flu strains.

“The world’s COVID-19 vaccine” that could end the pandemic

CORBEVAX is another protein subunit vaccine that has recently gained much attention. It was developed at the Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine by updating a vaccine previously created against SARS-CoV-1.

During the 2003 SARS outbreak, Baylor researchers created a vaccine by inserting the genetic information for a portion of the SARS virus spike protein into yeast to produce large amounts of the protein. After isolating the virus spike protein from the yeast, they added an adjuvant that helps trigger an immune response.

When SARS-CoV-2 emerged in 2019, they updated the spike protein to match the new coronavirus. A large clinical trial found the vaccine was safe, well-tolerated and over 90% effective at preventing symptomatic infections.

CORBEVAX development did not attract significant public funding, and the US$7 million needed for its development were provided by philanthropists.

The vaccine, which many believe could be a game-changer, is currently licensed patent-free to India’s largest vaccine maker Biological E. Limited (BioE), which plans to manufacture at least 100 million doses per month starting in February 2022.

The patent-free arrangement means that low- and middle-income countries can produce and distribute this cheap, stable and relatively easy-to-scale vaccine locally, potentially changing the course of the pandemic.

The universal vaccine

Several US institutions, such as the University of Wisconsin, Duke University, and Brigham and Women’s Hospital in Boston, are studying pan-coronavirus vaccines  – vaccines that can work against all coronaviruses.

Last month the US Army announced that its Spike Ferritin Nanoparticle (SpFN) COVID-19 vaccine showed promising early clinical results.

A preclinical study published in Science showed that the novel nanoparticle-based COVID-19 vaccine triggers a potent immune response in non-human primates. According to Defense One, the vaccine will soon undergo human trials.

Ferritin is an iron-carrying protein that forms a 24-unit sphere-shaped particle – like a soccer ball with 24 faces. The researchers can customise the vaccine for any coronavirus strains that arise by attaching the spikes of multiple variants to each face.

Although it is impossible to predict what the next variant will look like, we know it will arise from one that currently exists and preserve some of the spike’s features of its predecessor. A pan-coronavirus vaccine offers our immune system a broader library from which to draw information to recognise a brand new variant.

“It gives your immune system a broader spectrum of different variants,” says Balasubramaniam. “It’s like giving the immune system a lot of books on the same subject.”

A pan-coronavirus vaccine offers our immune system a broader library from which to draw information to recognise a brand new variant.

Dr Kayvon Modjarrad, director of infectious diseases at Walter Reed Army Institute of Research (WRAIR) and co-inventor of SpFN, told Defense One the team is testing the vaccine against all the different variants, including Omicron.

The unprecedented cooperation between different research groups worldwide and the support from regulatory bodies have made the speedy development of life-saving COVID-19 vaccines possible. But the first-generation vaccines did not end the fight against this pandemic. A second generation of vaccines that address current limitations and inequity is urgently needed.

Griffin is optimistic. “I expect second-generation vaccines [to be available] over this year or next year. They will bring us a very long way towards getting high levels of control against this virus and getting our life closer to what it was like before.”