9 min read.Updated: 18 Nov 2020, 12:02 PM ISTAnirban Mahapatra
A year from now, India is likely to be in the midst of a massive vaccination initiative. What’s the fine print?
There are long days ahead. But there’s reason to remain positive about prospects of getting vaccinated in India. In the meantime, continue to socially distance, wear masks and so on
WASHINGTON DC :
Imagine a very different Diwali 2021 from the one we just experienced this year. A year from now, India is in the midst of a massive vaccination initiative. You and your friends have been vaccinated and while social distancing, avoiding crowds, and facemasks are still necessary, the atmosphere is far more festive than in 2020.
If I’m getting your hopes up, then there’s good reason. We may be finally turning a corner on a pandemic after a year in which over 1.3 million have already died globally.
Anyone following the news knows by now that it’s been a good few days for covid-19 vaccines. On 9 November, Pfizer and BioNTech announced that their ribonucleic acid (RNA-based) vaccine was 90% successful in preventing symptomatic covid-19 after 94 cases in ongoing phase III human trials.
Later that week, Sputnik V, the viral-vector vaccine produced by Moscow’s Gamalaya Institute, was announced to be 92% effective (albeit after trials on only 20 reported cases).
Most recently, on 16 November, Moderna stated that its RNA-based vaccine was more than 94% effective at preventing disease on the basis of 95 cases in ongoing phase III human trials.
Vaccine development follows a standard trajectory. Preclinical trials are conducted in non-human primates such as rhesus macaques monkeys to see if the vaccine candidate should proceed to human trials. Phase I trials are conducted in a limited number of people to test for safety and to tweak doses. Phase II trials are conducted in broader groups of people to check for safety and effectiveness.
We are now seeing results from front runner vaccines that are in phase III trials. These trials are conducted in thousands of people. Some participants receive an actual vaccine. Others get a placebo. Then the number of cases of symptomatic covid-19 is counted and tracked back to whether participants received the vaccine or the placebo.
We want fewer people who receive the vaccine to be diagnosed with symptomatic covid-19 compared to those who receive the vaccine.
That’s because the vaccines being tested now are mainly checking for symptomatic disease (the trials do not include asymptomatic infections). In other words, they are not testing if vaccines prevent infections altogether. Second-generation vaccines which will come after the current group of vaccines is approved may be more suitable for the task of preventing infections.
But the results of the vaccines that we have so far are cause for cheer.
The US Food and Drug Administration has set 50% in preventing disease or infection as the baseline for effectiveness for a vaccine to be approved for use in the US. Dr. Anthony Fauci, head of the US National Institute of Health and Infectious Disease, had said that he wanted a vaccine to be at least 75% effective.
We have vaccines that are significantly better, even if the actual percentages are still subject to change. The interim data for the Pfizer and Moderna trials accrued very quickly after two doses of either vaccine or placebo had been administered to participants. Sputnik V garnered criticism for gaining official approval even before trials had been completed.
Different vaccines will have different effectiveness over time, but early indications are that the threshold will be met.
Some scientists have warned that we should be cautious before expecting too much from company press releases. After all, the interim studies are still underway and vaccine data has not been submitted to regulatory authorities.
None of the phase III results have been peer-reviewed. But we also need to put these interim results into broader context.
It is important to step back and think about the monumental achievement of creating effective vaccines that work for a never-before-seen virus causing a disease in under a year.
This is a fantastic achievement since vaccines typically take anywhere from five to 10 years to develop. This rapid pace has been due to the technological advances in the last few years and also due to the rational approach used to design the front runner vaccines.
The genetic sequence of the coronavirus was available in early January. The structure of the “spike" protein that allows it to infect cells was published shortly thereafter. Vaccines were created to thwart the virus from infecting cells by blocking parts of the spike protein.
What RNA vaccines do, for example, is that they instruct the host machinery to make a part of the viral spike protein that the immune system can use for target practice to build antibodies—much in the same way that it would after a real infection.
The fine print
How long will immunity from one of these vaccines last? It’s hard to say right now given the short duration of the trials. Typically phase III trials run for anywhere from one to four years. Researchers will continue to monitor immune response and any adverse effects of vaccination for years.
But there is some good news from natural infections. Researchers have shown that natural infection induces protective neutralizing antibodies that are detectable months later. We can expect that vaccination results in similar neutralizing antibodies. And long lasting T-cells may also play a role in immunity.
So which of these vaccines is best? We still don’t know yet. While both Pfizer and Moderna have enrolled thousands of patients, the diversity of the participants in each trial needs to be examined. For example, a vaccine that works best for an elderly patient may not be the one that is most suitable for a young child.
In the coming days, other companies will present their own interim phase III results. And we can hope that all of them work because the world will need many vaccines.
Moderna’s phase III clinical trials enrolled around 30,000 participants in the US and was generally well tolerated, with major side effects being fatigue, muscle pain, headaches, and soreness around the injection site. Participants in the Moderna trial were over the age of 18.
Moderna garnered the most enthusiasm for pointing out that its vaccine remained stable in ordinary refrigerators for a month and in freezers for up to six months. The company also noted out that its vaccine could prevent serious covid-19, with none of the 11 severe cases occurring in those who received the vaccine.
On the other hand, Pfizer’s phase III enrolled around 44,000 patients in the US, Brazil, and elsewhere.
Crucially their trial was later expanded to children over the age of 12. There are few vaccine trials that have enrolled children since severe disease is rare in this population; but controlling the spread of the virus is ultimately going to rely on the inoculation of children. The next interim analysis of this vaccine will be at 164 cases, in the coming days.
Pfizer-BioNTech’s vaccine is stable in freezers set to -70 degrees Celsius. This low temperature will present a challenge during the production and deployment stages.
Significant investment in cold chain management will be needed to ensure that this vaccine does not degrade prior to use. Pfizer is cognizant of this drawback and is working on a vaccine in powder-form that is stable when refrigerated.
The safety factor
Safety is another aspect that regulators will be looking at carefully. While most adverse reactions to vaccines occur shortly after vaccination, they can also occur much later. We may not know about the possibility of rare adverse effects until a few months after vaccination.
Safety and effectiveness data will be presented around two months from the second dose of the vaccines to the US FDA for an emergency use authorization. If authorized in mid-December, these vaccines will be available to those who fall in the highest priority category in 2020. They will likely be available to the broader public in early- to mid-2021.
At the same time, participants in these trials will be monitored for the length of immune protection and for any late adverse effects for two years.
One pitfall of RNA and viral vector vaccines is that manufacturing and distribution is behind vaccine development. How far behind is still anyone’s guess because no one has manufactured RNA and viral vector vaccines for millions of people.
Global manufacturing, distribution and delivery networks will have to pivot to newer vaccines platform and the process will take most of 2021.
By the end of 2020, Moderna expects it will have 20 million vaccine doses. They are planning 500 million to 1 billion doses in 2021. Pfizer plans up to 50 million vaccine doses in 2020 and 1.3 billion doses in 2021. Neither of these companies alone can scale up rapidly enough to meet the needs of the entire planet.
The actual effectiveness may decline over time as a result of waning immune responses. As more identified events accrue, the statistical effectiveness of vaccines will also change.
But there are many other vaccines in the pipeline as well. The key point is that we now have evidence that targeting the spike protein, which is what these vaccines do, is an effective way to produce neutralizing antibodies. Neutralizing antibodies are the kind of antibodies we want to prevent symptomatic infection.
So whether or not you or I get an RNA vaccine or a completely different vaccine altogether, the recent reports of effectiveness is good news.
Realistically, we can expect up to four billion doses of effective covid-19 vaccines next year, but that number is constrained not only by production capabilities for the vaccine, but also by the need for glass vials.
Wealthy nations have already initiated advance purchase agreements to obtain vaccines as soon as they become available.
However, an initiative of the World Health Organization, the Coalition for Epidemic Preparedness, and Gavi, called COVAX, plans to acquire two billion doses of covid-19 vaccines through 2021 for distribution in low- and middle-income countries.
In September, WHO director-general Tedros Adhanom Ghebreyesus said, “The first priority must be to vaccinate some people in all countries, rather than all people in some countries."
The India story
There are long days ahead. But there’s reason to remain positive about prospects of getting vaccinated in India. The AstraZeneca/ Oxford University vaccine is in phase III clinical trials in India and should report interim results imminently. If safe and effective, Serum Institute of India will offer 200 million doses of this vaccine to India and to certain countries.
Novavax also has an agreement with India’s Serum Institute of India for 1 billion doses for India and other low and middle-income countries. All in all, Serum Institute of India plans to produce five vaccines for India and low and middle-income countries.
ZydusCadila and Bharat Biotech are two Indian companies that have vaccine candidates in phase II clinical trials.
Union health minister Dr Harsh Vardhan has said that India could begin broad vaccinations in early 2021, with the goal of vaccinating up to 250 million people by midyear.
What should we do while we wait for our turn to get vaccines? We will have to continue to socially distance, wear masks, avoid crowds, and wash our hands. There’s a popular saying among immunologists that bears repeating: vaccines don’t save lives, vaccinations do.
Until we are vaccinated, it doesn’t help us personally; in conjunction until a sizeable percentage of the population is vaccinated, we won’t see a broader effect on the unvaccinated either.
The good news is that while we wait, new treatment options for covid-19 are also becoming available. Just last week the first monoclonal antibody (created by Eli Lilly) received emergency use authorization in the US for the treatment of early stage covid-19. There are other monoclonal antibodies which may be approved in the coming days.
Already 2021 looks like it will be much better than 2020.
Anirban Mahapatra, a microbiologist by training, is the author of 'Covid-19: Separating Fact From Fiction' to be published in February 2021. These are his personal views.