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Encouraging signs from initial Covid-19 vaccine trials
BY ANTHONY KING11 AUGUST 2020

There’s been a surge of data emerging from Covid-19 vaccine trials. The studies are mostly Phase 1 safety trials, but can give some hints of immune response to the vaccines. At the same time, trials in which animals are immunised and then deliberately exposed to the virus give positive indications of potential protection. However, we still don’t know what level of immune response will be protective for humans, nor how long that protection will last.



Source: © Felix Dlangamandla/Beeld/Gallo Images/Getty Images

As initial data shows the vaccines are safe and elicit positive immune responses, companies are racing to start larger trials in areas where the virus is most prevalent to determine its efficacy

The acknowledged leader is the candidate from the University of Oxford, UK, which is a chimp adenovirus vector (ChAdOx1) expressing the entire spike protein of Sars-CoV-2. A randomised controlled trial of over 1000 healthy adults showed an encouraging antibody and T cell response.1 The vaccine is to be manufactured by AstraZeneca.

‘Both arms of the immune system were very well stimulated, including a very good T cell response,’ says Adrian Hill, director of Oxford’s Jenner Institute. The immune response, especially in terms of neutralising antibodies, was significantly increased by a second dose. That will be influential in planning future trials and any eventual rollout, Hill confirms.


The big question is how strong an immune response you need to induce protection

ADRIAN HILL, UNIVERSITY OF OXFORD

The levels of antibodies or T cells needed for protection are as yet undetermined, points out Dennis Burton, an immunologist at the Scripps Research Institute in La Jolla, US. ‘That is the acid test for any vaccine,’ he says. It’s likely that T cells in particular will be important for long-term protection.

China’s CanSino Biologics reported results on the same day as Oxford from a study that administered two different doses of its adenovirus-type 5 (Ad5) vectored vaccine in a trial of 600 volunteers in Wuhan.2 Ad5 is relatively common in humans, and 52% of the trial participants already showed antibodies against it, but levels of Ad5 immunity will vary in different populations. People with high existing antibody levels to Ad5 produced around half as many antibodies to Sars-CoV-2. The T cell response was similar in those with and without pre-existing antibodies to Ad5.

The only other adenoviral vaccine on the market in Europe is for Ebola, approved on 1 July 2020. Scientists in Europe and the US have given Ad5 a wide berth, since an experimental HIV vaccine, developed by Merck & Co, appeared to increase rates of HIV infection. ‘The Chinese and Russians clearly did not believe [the data]. For the 2014 Ebola outbreak, they made Ad5 vaccines and both got licensed in their respective countries,’ says Hill.

Moderna, Pfizer, Sinovac

Also in July, Moderna finally reported full data from the Phase 1 trial of its mRNA vaccine.3 Researchers have expressed annoyance at the company’s tendency to press release headline results, rather than publish full datasets. Moderna has ‘dribbled out small amounts of data over time, which is frustrating and unhelpful,’ says Gregory Poland, director of vaccines research at the Mayo Clinic in Minnesota, US.

Its trial of 45 healthy adults tested two vaccinations of mRNA encoding the spike protein, 28 days apart. Binding antibodies to the spike protein increased rapidly after the first vaccination, and again with the second dose. Moderna is to begin a Phase 3 trial with the US National Institutes of Health, involving approximately 30,000 volunteers.

More than half of Moderna’s volunteers experienced minor side effects such as fever, chills, fatigue, headache and pain at the injection site. This is relatively common with vaccination. For the Oxford group, there were enough fevers and systemic side effects that the trial protocol was modified to include paracetamol before vaccination.

Earlier in July, Pfizer and BioNTech reported on their mRNA vaccine candidate, which encodes the receptor binding domain of the spike protein, encapsulated in a lipid nanoparticle. The preprint described a robust T cell and a strong antibody response4 in 60 participants in Germany who received either one or two doses. Since then, the companies have announced that a different vaccine candidate, which encodes the entire spike protein, is to start a Phase 2/3 study.

‘The caution here is that these vaccine platforms have never been licensed before in humans,’ notes Poland. In a larger trial with 20,000 people receiving active vaccine, a serious side effect that occurs in one in ten thousand people might be missed, he warns. Regulators will have to decide what compromises and level of risk is acceptable.


The fact a vaccine induces an immune response is not proof that it will prevent infection

GREGORY POLAND, MAYO CLINIC

Sinopharm and Sinovac’s inactivated virus candidate is also advancing to Phase 3 trials. It will be given to over 8000 healthcare workers in China, as well as trials in the United Arab Emirates and Brazil. ‘This is super old technology, and it is often hard to grow the virus, which is why rabies vaccine is so expensive,’ says Hill. For some, this brings advantages. ‘We know how to deal with the inactivated approaches,’ says Florian Krammer, immunologist at the Icahn School of Medicine in New York City, US. ‘We don’t have a single RNA vaccine on the market.’

This strategy tends to require two or three vaccine doses, and often an adjuvant such as alum to bolster the response. ‘[The World Health Organization is] not so keen on those vaccines,’ says Hill. This is mainly because when vaccines for Sars were tested in animals, there was some evidence of antibody-dependent enhancement – in which exposure after vaccination can lead to more severe disease. ‘I don’t think this is a major concern at this point,’ says Burton of the Covid-19 candidates.
Up to the challenge?

Early vaccine trial reports prompted a rash of optimistic headlines. ‘The big question is how strong an immune response you need to induce protection,’ says Oxford’s Hill. ‘Most people [are focusing on] neutralising antibodies, because they don’t induce high levels of T cells, but we do.’ Nonetheless, the responses from different aspects of the immune system necessary for protection remain unclear.

‘The major concern remains efficacy, and the durability of efficacy, which is why these Phase 3 trials will be so critical,’ says Poland. ‘The fact a vaccine induces an immune response is not proof that it will prevent infection. Many companies have got to this point and failed in Phase 3 trials.’ In the case of Ebola, inducing small amounts of antibodies with vaccine was enough to provide protection. Whereas even the highest antibody levels to malaria do not offer a strong defence on their own.

I was quietly pleased. The vaccines did what they said on the tin. So far, so good

DANNY ALTMANN, IMPERIAL COLLEGE LONDON

To try and get a handle on how these immune responses might translate into protection, researchers are conducting challenge studies. These involve animals – in this case mostly primates – being either infected or vaccinated and then deliberately exposed to the virus. One such trial, led by Dan Barouch at Harvard University, US, in May showed that macaques challenged with Sars-CoV-2 five weeks after an initial infection displayed strong resistance to the virus.5 A second paper revealed that macaques given a series of DNA vaccine candidates also appeared to have good protection when challenged with the virus.6 ‘We are trying to race into vaccines [for Covid-19], but we haven’t got a clue what the correlates of protection are,’ says Danny Altmann, an immunologist at Imperial College London, UK. Animal studies can provide some insights into where that bar lies.

Challenge trials in macaques conducted by Janssen,7 Oxford,8 Moderna,9 Sinopharm–Sinovac10 and Inovio11 have all produced some level of protection, although the precise details vary. ‘There are half a dozen groups trying to zoom into Phase 3 trials where the stakes and costs are high,’ notes Altmann. He says the animal data support all the vaccines as plausible candidates. ‘I was quietly pleased. The vaccines did what they said on the tin. So far, so good,’ says Altmann. ‘The Oxford one stands out in the rip-roaring levels of T cell immunity that they showed,’ he adds.
Lasting protection

With the coronaviruses that cause the common cold, immunity starts to wane around 80 days after infection. Burton, however, argues this is irrelevant. ‘They are two separate things,’ he says. ‘A vaccine can do a lot better than a natural infection.’ Burton describes the early results from the mRNA vaccines as promising. We can make guesses as to how long the response will last, he says, ‘but you have to put the vaccine into people to understand what happens in a larger population’. The spectrum of possible outcomes include preventing transmission entirely, preventing infection or just preventing an infection from developing into the disease. ‘If we had a vaccine that could prevent the disease in large numbers of people, that would be very welcome,’ says Burton.

Results from the Oxford­–AstraZeneca Phase 3 trials in the US, Brazil and South Africa could be available by September–October if all goes well. With five other candidates also already in Phase 3 trials, Burton believes that efficacy data for several vaccines will become available before the end of 2020, but warns against predictions. ‘In this whole pandemic, a lot of things have been done faster than one would have imagined even six months ago,’ he says. ‘But this is a new pathogen and nature may have lots of surprises along the way.’

References

1. P M Folegatti et al, Lancet, 2020, DOI: 10.1016/S0140-6736(20)31604-4

2. F-C Zhu et al, Lancet, 2020, DOI: 10.1016/S0140-6736(20)31605-6

3. L A Jackson et al, N. Engl. J. Med., 2020, DOI: 10.1056/NEJMoa2022483

4. U Sahin et al, medRxiv, 2020, DOI: 10.1101/2020.07.17.20140533

5. A Chandrashekar et al, Science, 2020, DOI: 10.1126/science.abc4776

6. J Yu et al, Science, 2020, DOI: 10.1126/science.abc6284

7. N B Mercado et al, Nature, 2020, DOI: 10.1038/s41586-020-2607-z

8. N van Doremalen et al, Nature, 2020, DOI: 10.1038/s41586-020-2608-y

9. K S Corbett et al, N. Engl. J. Med., 2020, DOI: 10.1056/NEJMoa2024671

10. Q Gao, Science, 2020, DOI: 10.1126/science.abc1932

11. A Patel et al, bioRxiv, 2020, DOI: 10.1101/2020.07.28.225649

A coronavirus vaccine is on the horizon, thanks to a key discovery by these researchers

by Lara Korte

Credit: Pixabay/CC0 Public Domain

When the latest coronavirus emerged, Jason McLellan and his team were ready to take action.

McLellan, an associate professor of molecular biosciences at the University of Texas, has been studying respiratory diseases for years. In 2017, McLellan's postdoctoral researcher Nianshuang Wang identified genetic mutations necessary to stabilize a key component of diseases like MERS, also a coronavirus.

So when Chinese researchers shared the genetic sequence of the new coronavirus on Jan. 10, UT researchers were able to quickly map the virus and inject it with previously-discovered mutations, allowing the researchers to freeze a key protein in a way that would become essential for creating a vaccine.

"Now every pretty much everybody's using them," McLellan said. "I think four of the five leading coronavirus vaccines all contain the stabilizing proteins my lab designed."

Several major companies, bankrolled by billions of dollars from the federal government, are in a race to complete clinical trials for their version of a coronavirus vaccine. It can normally take years for a vaccine to pass through clinical tests before it becomes available to the public, but the process has been expedited over the past several months for coronavirus vaccine candidates from companies including Pfizer, Johnson & Johnson, Novavax and Moderna.

The vaccine candidates are either in or close to the final stages of clinical trials before final authorization by federal drug authorities, and all four are using the UT team's discovery in their vaccine formulas.

"It's really exciting," McLellan said. "It's like everything I hoped for when I wanted to start doing research."

The success of the UT team's discovery hinges on the ability to map and identify what McLellan called the "Achilles' heel" of the coronavirus—the protein spike. This protein is the part of the virus that fuses onto healthy cells and transmits the infection. Researchers used mutations from earlier research to freeze the protein in its pre-fusion form. By putting a pre-fusion version of the protein into a vaccine, a person's immune system is trained to identify the virus before it latches onto cells, and create antibodies to fight it off.

"Antibodies need to recognize elements that are on the outside of the virus because they can't get inside of the virus," McLellan said. "So the spike is this massive entity on the outside of the virus, and it needs the spike in order to attach and fuse to cells, and if you stop either of those, you stop viral entry."

The researchers designed the necessary mutations within about a day of receiving the coronavirus genome. The McLellan lab completed the atomic-level structure, and graduate student Daniel Wrapp harvested and purified the spike protein.

Researchers at the National Institute of Allergy and Infectious Diseases, who are working on the Moderna vaccine, published the results of their Phase 1 trials with mice on Wednesday. The paper reported that the use of McLellan's stabilized spike protein elicited a positive immune response and prevented coronavirus infections in the lungs and noses of mice.

Moderna began its crucial Phase 3 testing late last month and plans to include 30,000 subjects from 89 centers around the U.S. It could be several months before the results of the study are clear.

A spokesman for the university said researchers so far have not received any payment for the use of their research in vaccine candidates. However, UT and the scientists may eventually see monies from licensing and royalties. The details are still being worked out between the university, the National Institute of Health and the drug companies, the spokesman said.

Meanwhile, the federal government is investing in mass production capabilities, with the hopes that one of the vaccine candidates will be viable by the end of the year. Last month, President Donald Trump announced a $265 million deal to secure manufacturing resources at a plant in College Station for the Novavax vaccine candidate. If Novavax makes it through clinical trials, the majority of its doses will be produced in Texas.

©2020 Austin American-Statesman, Texas
Distributed by Tribune Content Agency, LLC.