Syringes to administer the Pfizer-BioNTech COVID-19 seen at a nursing home in Burgbernheim, Germany, December 28, 2020. Photo: Hannibal Hanschke/File photo.

Vaccines have never enjoyed as much attention and time in the limelight as they’re getting now. Never in history have we been able to make vaccines against a disease so fast, never have we tested so many new platforms to develop them, and never have we contemplated as mammoth an exercise as we are today to vaccinate billions of people.

As things stand, at least 20 vaccine candidates are undergoing phase 3 clinical, three have been approved for wider use, and seven for early, limited use. Around 25 million doses of different COVID-19 vaccines in 50 countries have been already administered thus far.

Last week, India also approved two COVID-19 vaccine candidates, AstraZeneca’s Covishield and Bharat Biotech’s Covaxin. The Union health ministry has said the vaccination drive will commence from January 16.

But in spite of all of these developments, there are still some questions that haven’t been answered. Here are 13.

1. Are all COVID-19 vaccines equal?

Researchers have noticed considerable differences between key vaccine candidates in non-human primate and human clinical trials. All vaccinated monkeys administered Covishield developed COVID-19 when infected with the novel coronavirus. In contrast, Janssen’s Ad26.COV2.S candidate and those that used inactivated viruses appeared to resist infection better.

The Novavax vaccine candidate elicited the most anti-S-protein antibodies, followed by those of Moderna, Sinopharm and Janssen. At the other end was Sinovac’s vaccine candidate.

Not all vaccine candidates are going to be successful. One developed by researchers at the University of Queensland was pulled back after its recipients tested falsely positive for HIV.

All vaccine candidates have been found to be efficacious against severe infections than against milder ones. The makers of the mRNA vaccine candidates have reported better efficacy than those of inactivated candidates. Not all viral vector vaccine candidates have the same efficacy (e.g. Gamaleya’s Sputnik V is reportedly more efficacious than Covishield).

In addition, the mRNA and viral vector vaccine candidates have been found to be more reactogenic than their inactivated counterparts (reactogenicity is the ability of a vaccine to produce ‘expected’ adverse reactions, like soreness at the point of injection).

Novavax’s recombinant protein vaccine has shown great potential in both non-human primate and early human phase 1/2 trials, although its true test will be in phase 3 trials.

2. Some are anxious over future genome integrations and mutations with some COVID-19 vaccines candidates. Are these concerns justified?

Broadly, two types of COVID-19 vaccine candidates can enter a human cell’s nucleus. They are viral vector and DNA vaccines. DNA vaccines don’t alter a person’s DNA at all. They provide a temporary addition to a small number of cells. They don’t enter the genome but merely imitate what happens when we get infected by a virus.

A virus inserts its DNA into our cells to allow it to replicate and spread. A vaccine can do that as well – but in a controlled manner. During a viral infection, genetic material (DNA or RNA) from the virus is present inside our cells, but most viral infections don’t then leave DNA that becomes part of the genome. HIV, for instance, has an enzyme, called reverse transcriptase that copies the virus’s genetic material back into the genome. Viruses like the SARS-CoV-2 or influenza don’t have this enzyme.

However, researchers have previously reported that people with a preexisting immunity to adenovirus type-5 vectors had an increased risk of acquiring an HIV infection after receiving an experimental Ad5-vectored HIV vaccine.

3. Will the current generation of vaccines be effective against a mutated variant of the novel coronavirus?

SARS-CoV-2 mutates regularly, acquiring about one new mutation in its genome every two weeks. In the ‘UK variant’, designated B.1.1.7, there are 23 mutations, including eight in the spike protein. The main mutation is N501Y, which may make the receptor binding stronger and allow the virus to spread better. The ‘South Africa variant’ has three mutations in the spike protein’s receptor binding domain (RBD), and could post a greater challenge than B.1.1.7.

Researchers have found no major changes in neutralisation by N501Y in the UK variant. A study funded by Pfizer suggests its vaccine candidate is effective against this strain of the virus as well.

However, according to another study, the E484 mutation of the ‘South Africa variant’ greatly reduces neutralisation in some individuals – i.e. human antibodies are less effective against this strain.

This said, the effects of mutations differ across individuals, and not everyone is affected similarly by RBD mutations. Sometimes, the effects of mutations change over time for the same individual, as the individual’s immune response matures.

What do these results mean for new variants?

Mutations like E484K are certainly of concern. However, they reduce neutralisation activity – not eliminate it entirely. A virus would need to evolve for many years to be able to evade neutralisation in most people.

So the current vaccines will be useful for quite a while. There is no need to panic. The virus uses its own genetic material to manufacture amino acids that are strung together to make proteins. And thus far, fewer than 1% of the novel coronavirus’s spike protein amino acids have been affected. The virus will need to accumulate many, many more mutations to be able to have a major impact on vaccines.

For example, all the vaccine candidates licensed thus far are polyclonal – producing different antibodies and T-cells that target several parts of the spike protein. The virus will likely need to accumulate multiple mutations corresponding to the spike protein alone to evade immunity induced by vaccines or by natural infection.

SARS-CoV-2 may undergo antigenic drift, and we may need to update the strain we use in our vaccine candidates regularly. (Antigens are a collection of proteins expressed on the virus’s surface, based on which antibodies register the virus’s presence. Antigenic drift is a change in the composition of these proteins due to mutations.) Even if major changes occur in the RBD and a new strain emerges, vaccines based on nucleic-acid technology could be adapted to tackle them in a few weeks or so.

4. Would inactivated vaccines like Covaxin be more effective against new variants of the virus?

This is a speculative question. Inactivated vaccines have a larger repertoire of immunogens – the substances that provoke an immune response – than mRNA vaccines. However, most immune responses are targeted against the virus’s spike protein, so there should be no difference.

Hypothetically, an inactivated vaccine is also more liable to elicit antibodies that may not have strong neutralising potential, and may result in antibody-induced disease enhancement (ADE). Put differently, in ADE, the antibodies in the body could make the disease worse, instead of battling it.

5. Is it advisable to administer the second dose of Covaxin to a person who has already received a single dose of Covishield?

Although clinical trial data indicates Covishield is effective, there has been no study on the interchangeability of vaccines between doses.

It’s always advisable to complete the vaccination schedule with the same brand of vaccine, and avoid switching brands.

6. How common are reinfections with SARS-CoV-2, and how long does vaccine-induced immunity last? Will we have to take booster shots frequently?

Healthcare workers have been reporting more and more cases of reinfection. But how common reinfections really are and how long serum antibodies and virus-specific T-cells persist after infection are still unclear.

For many other respiratory virus infections, including influenza and seasonal coronaviruses that cause colds, serum antibodies persist for a few months to a year, and reinfections are quite common. Reinfection with viruses that cause systemic infections with viraemia, such as measles, mumps, rubella, hepatitis A, yellow fever and polio (with the same serotype) is uncommon.

In contrast, reinfection with viruses that cause mucosal infections without viraemia, like respiratory syncytial virus, is common.

7. What are the implications of reinfection with SARS-CoV-2?

Previously infected persons may need to be vaccinated. Herd immunity from infection is unlikely to be sufficient to eliminate the virus if reinfection is common. The second infection is also likely to be milder, although not necessarily so.

Vaccination may not provide lifelong immunity and booster shots may be required.  Perhaps the annual quadrivalent flu vaccine could include a vaccine for SARS-CoV-2 as a component.

8. How durable will vaccine-induced immunity be?

As of today, nobody has an answer to this question. Most recent reports suggest natural infections provide immunity for three months or so and memory B-cells are present for around eight months. COVID-19 vaccines – especially those that induce a strong neutralising antibody response – should at least provide this much protection.

This said, if researchers expect to develop a concrete answer, they should follow up on vaccinated people for at least 1-2 years. Thus far, we only have efficacy data based on 2-3 months’ follow-ups.

9. Will the new COVID-19 vaccines provide sterilising immunity and halt the transmission of viruses?

In animal studies involving non-human primates, researchers found that most vaccines protect only against infection of the lower respiratory tract, and may not induce sterilising immunity in the upper respiratory tract.

The trials of Moderna’s and AstraZeneca’s Covishield vaccine candidates suggested that they could prevent asymptomatic disease and provide mucosal immunity, which may have some effects on transmission.

10. Will intranasal vaccines be more efficacious?

Vaccines that are given by the mucosal (intranasal) route may have an advantage in the form inducing higher levels of local immunity, and could result in tissue resident T- and B-cells.

Studies of SARS-CoV-1, SARS-CoV-2 and MERS vaccines in animals indicate that intranasal vaccination was more effective in many studies compared to intramuscular vaccines. Unfortunately, very few intranasal vaccines for COVID-19 are currently going through clinical trials.

11. Will a single dose of a two-dose scheduled vaccine be effective?

Both the Pfizer and Moderna vaccine candidates may provide reasonable protection after the first dose. Their clinical trial data suggests significant protection even without a second shot.

Moderna reported the efficacy of the first dose of its candidate to be 80.2% (in preventing COVID-19 two weeks later). In both vaccine candidates’ trials, 10-14 days after the first dose, researchers noticed a sharp drop in the disease’s prevalence in the vaccinated group.

Data for Covishield also indicates it is significantly efficacious after the first dose. However, we still don’t know how long the protection after a single dose will last. Pfizer has already warned that they have no evidence their vaccine candidate will continue to protect against COVID-19 if the booster shot is delayed by more than the duration tested in the trials.

12. How well will older individuals, who are more at risk of developing severe COVID-19, respond to the vaccine candidates?

The data thus far suggests the Moderna vaccine candidate works better among younger people. The vaccine efficacy was 95.6% for participants aged 18-65 years and 86.4% for participants aged 65 years or more.

In those aged 18-55 years, the majority showed a slight decrease in neutralising antibodies in three months following their second dose. However, among those aged 56-70 years and 71 years or more, neutralising antibodies fall by 50-95%.

These figures suggest that among older people, the duration of neutralising antibodies from the Moderna vaccine will be relatively short – potentially less than a year. AstraZeneca has not yet analysed Covishield’s data vis-à-vis older recipients.

13. Will children need COVID-19 vaccines?

Children will need to be vaccinated at the later stages. This said, the new ‘UK variant’ has precipitated many cases of COVID-19 among children.

One important issue to keep in mind is the vaccine candidates’ tolerability. Children usually show greater reactogenicity than adults. Many vaccine candidates also have relatively strong side effects, so researchers may need to develop low-dose vaccines for this age group, especially for viral vector and mRNA vaccines.

Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Center, Bijnor.



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