The long road to the perfect covid vaccine


January 2022 seems like a déjà vu of 2021: citizens exhausted with covid restrictions; healthcare workers pleading with those suffering from mild symptoms to stay at home and leave hospital beds for those who really need them. In quick time, the definition of a fully vaccinated person has changed to someone who has received three doses. Many countries are exploring a fourth dose for the elderly and the immuno-compromised. So, what really is the future of covid-19 vaccines?

If the vaccines of year 1 of the pandemic were approved based on their efficacy in reducing the possibility of infection, severe disease and death, the next generation of vaccines would likely be judged based on their ability to offer longer protection against infection. Specific vaccines for the pediatric population is another area of emerging interest where multiple companies are racing towards the finish line.

Vax pipeline

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Vax pipeline

Over 9 billion doses have been administered over the past year using eight different vaccines. Data from the World Health Organisation show that there are 60 vaccine candidates currently in phase 3 of clinical trials—an indication that the quest for an improved and effective vaccine against covid-19 has only just begun.

Last month, Indian drug regulators approved Covovax and Biological E’s Corbevax, taking the total number of vaccines approved in the country to eight. Despite having one of the largest baskets of locally available covid-19 vaccines, India has until now used only two—Covishield and Covaxin—in its national immunization program. For the developers of Covovax and Corbevax, the challenge would be to convince governments that their offering can deliver superior performance compared to the existing vaccines, either as a booster or as a standalone dose.

Dr Peter Hotez and Dr Maria Elena Bottazzi, who developed the Corbevax vaccine in partnership with Biological E, told Mint that they see the potential for their vaccine as a standalone, booster as well as for pediatric use.

“Only 40% of India is (fully) vaccinated. So, there’s still a long way to go,” Hotez said. “As a booster vaccine, this (Corbevax) can help particularly because in certain instances you cannot give adenovirus-based vaccines (AD) (like Covishield) as a booster… because you make antibodies to the AD virus.”

Dr Bottazzi believes that Corbevax might also hold up against the Omicron variant and might offer longer spells of protection, which most of the current vaccines—including the much-hyped mRNA-based vaccines—have not been able to do.

“We are learning that after the initial excitement about the mRNA vaccines, there may be issues with long-term performance and long-term durability of protection. We are seeing that within a couple of months after a booster shot, the protection against the Omicron variant plummets significantly—from 70% to 30%”, explained Dr Hotez. “Now, we have to see if there is an inherent problem with the mRNA platform or is this is a variant-specific concern that could be fixed as the mRNA technology matures.”

Covovax and Corbevax are second-generation protein-based vaccines, which are made using specific particles of a virus— known as antigens—that can then generate an immune response. The antigens are combined with an ‘adjuvant’ to trigger the immune response. Existing vaccines used to prevent diseases such as Hepatitis B are among the most common examples of this platform.

The hype fades

A year ago, mRNA-based vaccines manufactured by Pfizer and Moderna became the benchmark for covid-19 vaccines. Their technology did not use any real virus particles, which made them one of the safest platforms to use.

The over 95% efficacy in clinical trials—considerably higher than adenovirus vector or inactivated whole-cell vaccines—made the mRNA vaccines a coveted shot. The hype around them led governments in the West to stockpile these vaccines resulting in revenues of over $40 billion to Pfizer and Moderna in the pandemic year.

But as Dr Hotez points out, the euphoria over the mRNA platform seems to be fading as the level of protection against the Omicron variant in particular—even as a booster dose—doesn’t seem to be very high. “This is why you don’t go into a global pandemic with an all-new technology and that is why we always felt the need to balance it with more traditional technology, such as the recombinant protein vaccine which has that track record of durability”, Hotez said.

There is no definitive data yet on booster effectiveness as it has only been a couple of months since countries in the West started their booster policy. The modelling data from UK’s Imperial College of London indicates that boosters are 85% effective against Omicron in preventing severe disease. But what is becoming clear with emerging breakthrough infections is that Omicron evades the humoral response even in doubly vaccinated individuals

As a result, vaccine experts are now coming to a consensus on the fact that some traditional vaccine approaches could be needed to fight future variants that seem to be inevitable and unknown for now.

“Maybe these (mRNA-based) vaccines had a role (to play) at the beginning of the pandemic. It would have been nice if we had (a) balance (right) from the start so that we did not have to come (in) late in the picture”, said Dr Bottazzi. “The pandemic is very different than what it was last year, but it is shifting. Maybe, we do have to rely on conventional technology, but look at not just how they work but also how they are recalling (the) memory (of infection)… and how they can be made in a cost-efficient way.”

Future pipeline

The tepid interest in scaling up the mRNA platform is also showing up in the future pipeline of covid-19 vaccines. Most vaccine candidates that are currently in phase 3 trial are protein-based vaccines, followed by the adenovirus vector-based ones and then comes the mRNA-based vaccines.

Omicron has inevitably changed how companies look at vaccine development. Though the current crop of vaccines is holding up against severe disease and deaths, the elusive goal of stopping transmission remains the target of vaccine makers.

“The primary metric should be to look at vaccines that (can) prevent severe diseases. But we should also aim to manufacture vaccines that (can) reduce overall infection or (even) mild infection”, said Dr Sanjay Pujari, director and chief consultant, Institute of Infectious Diseases, in an interview with Mint last month. Pujari added that for future vaccine development, there will be three approaches. Besides developing vaccines that reduce overall infection, a variant-specific vaccine similar to the seasonal flu shots and a pan-coronavirus vaccine that would work against all seasonal coronaviruses could become the new frontiers of research.

“I won’t be surprised if companies start looking at Omicron-specific vaccines. Covid19 is not over as long as (the) variants are still around,” said Davinder Gill, former CEO of Hillman Labs, the organization that uses innovative tech to develop vaccines for global health. “The next variant (will) most likely be built off Omicron and it is possible that with those variants, we will have to go back to drawing rooms”, Gill added.

Ultimately, the holy grail in covid-19 vaccine research is developing a pan/beta coronavirus vaccine that could potentially protect against all emerging variants. The idea is to target coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS).

Blanket protection

Norway-based Coalition for Epidemic Preparedness Innovations (CEPI) has already announced funding to two companies—MigVax and Vaccines and Infectious Disease Organization of the University of Saskatchewan—to provide proof of concept for a “variant proof” vaccine that can tackle ‘beta coronaviruses’. These attempts are in the initial stage of proof-of-concept but the idea is to find means to protect humans against new variants of concern.

“The threat of new variants emerging which can evade the protection of our current vaccines and set the global response back to square one continues to hang over all of us”, Richard Hatchett, chief executive officer, CEPI, said in November last year while announcing the funding for the beta coronavirus vaccine research. “That’s why developing globally accessible vaccines which are broadly protective against covid-19 variants is imperative for global health security.”

Baylor College of Medicine, too, is working on a pan coronavirus vaccine now that there is a renewed interest in the space. “We were working on it pre-covid. But when we were trying to get our funding renewed for SARS/MERS pan coronavirus vaccine, we got a response saying it has no innovation, and that (it) was not a priority,” Dr Bottazzi said. Now, the researchers in her organisation are working on new strategies such as multivalent vaccines that combine proteins from different lineages.

But as the array of vaccines expands, questions on what the public will trust will remain.

The debate on vaccination and its limited role in ending the pandemic has already gained momentum with the rise in new infections. After mandating vaccination for travel and employment purposes, with Omicron and the call for further booster doses, governments face an uphill task in keeping the public health message effective and simple.

“The public is losing trust in vaccines but I feel certain that over time trust will build and most people will be vaccinated,” said Lawrence O. Gostin, Faculty Director, O’Neill Institute for National and Global Health Law, in an email to Mint. “The problem was that public health officials promised that vaccines would prevent infections, but the Omicron variant has shown that vaccines don’t do a particularly good job at preventing breakthrough infections. We have to change the public health message.”

Gostin added that in future, governments should not promise that vaccines will significantly reduce covid-19 cases. Instead, the message should be that the crucial value of vaccines is in preventing the vaccinated people from getting very sick, being hospitalized, or dying.

The message that seems to be echoing across the public health field is that vaccination alone is not enough to end the pandemic; they prevent deaths but remain inadequate in cutting the chain of transmission and hence we need other interventions like antivirals along with vaccines.

“By the end of 2022 or early 2023, covid-19 may become like seasonal influenza in some countries. We will probably have to vaccinate at least seasonally and rely on our health system to have good treatments for those who do get ill,” said Gostin.

However, the end game, he says, is that we just stop caring and live our lives as normally as we can.

“Remember, after the Great Influenza pandemic of 1918 came the ‘Roaring 20s’. Humans are social animals and we will return to doing all the things we love.”

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