Vaccine Vexations

THE MONTH OF March is named after Mars, the Roman god of war. In the earliest Roman calendar, it signalled the beginning of the warfare season. The month also has special significance in the war against Covid-19. On March 11th, 2020 the World Health Organization (WHO) upgraded Covid-19 from a Public Health Emergency of International Concern (PHEIC) to a pandemic. India also went into a nationwide lockdown on March 25th, 2020, which lasted 68 days. It ‘flattened the curve’ and allowed time to build capacity but created a host of associated problems.

The number of new daily cases in India had been falling for a few months, raising optimism that the pandemic was well behind us. We had demography on our side—more than 50 per cent of Indians are below 25 years of age, and we had ready access to two vaccines. But the virus made a strong comeback in March 2021, starting a fresh battle. In the six weeks since mid-February this year, daily cases in India have increased from about 11,000 to over 58,000 based on a seven-day moving average. On March 28th, India also crossed 12 million confirmed cases. While it took 66 days to go from 10 to 11 million cases, it took only 34 more days to reach 12 million.

Several countries, including the US, the UK, Israel and others, have effectively deployed vaccines to curb the pandemic and
reduce mortality. India would have to do the same. Vaccination started in India on January 16th when cases were at a daily low but did not pick up as expected. Ten weeks later, 53.4 million people have received one dose and 8.5 million have received both doses. This amounts to just 3.9 per cent and 0.6 per cent, respectively.

A vaccine is a biological preparation that provides active immunity to a disease-causing agent (also called a pathogen). It typically contains something that resembles the pathogen—this could be a weakened (attenuated) or killed pathogen, one of its toxins or a protein that covers its surface. The vaccine stimulates the body’s immune system to recognise the pathogen, destroy it and retain a memory for future encounters. Antibodies that develop after infection or vaccination recognise the pathogen, prevent its entry into cells, and tag it for destruction. Some vaccines also induce killer cells that seek out and destroy reservoirs of infected cells.

It used to take years to develop a vaccine. The chickenpox and nasal flu vaccines took 28 years to make, the human papillomavirus and rotavirus vaccines took 15 years, and paediatric combination vaccines took over a decade to develop. However, multiple Covid-19 vaccines were developed and approved for use in less than a year. How was this possible? It confuses many, who think that speed compromised the safety and effectiveness of these vaccines.

There are several reasons for this—science, luck, logistics and economics. Science contributed with the ready availability of multiple vaccine development platforms, which were quickly repurposed for Covid-19 vaccines. And luck played its part. All vaccines are based on raising immune responses to the spike protein of the virus, and this worked very well. Scientists have been working on an HIV/AIDS vaccine for almost four decades and all approaches that use the virus’ surface protein have so far failed to produce an effective vaccine. In pre-Covid times, vaccine development progressed sequentially—from research to pre-clinical (animal) studies to clinical development—followed by approval and then largescale manufacture. However, regulators allowed many overlapping or parallel steps for Covid-19 vaccines and regulatory reviews were done with speed. Finally, companies were allowed to manufacture vaccines prior to their approval. For example, the Serum Institute of India (SII) had already produced 40 million doses of its Covishield vaccine ahead of regulatory approval. Innovative international funding models such as Covax, which provided $300 million to SII and assured orders ahead of approval, helped offset some of the financial risk.

Efficacy remains a poorly understood term. It is a measurement of how much a vaccine lowers the risk of symptomatic Covid-19 disease. It also depends upon the details of the trial. It is tested in a representative population under highly controlled conditions. But the effectiveness changes when the vaccine moves out into the population

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The genomic sequence of SARS-CoV-2, the virus that causes Covid-19, was revealed and isolated on January 7th, 2020. In 42 days, a US biotech company called Moderna produced an RNA vaccine ready to be tested on humans; in 63 days, the first human volunteer was given a test dose of this vaccine. A small German biotech company called BioNTech produced a similar vaccine and partnered with the American pharmaceutical giant Pfizer to co-develop it. RNA vaccines had never been tried earlier but worked remarkably well. They work by going into our cells, producing the protein (spike in this case), which raises immunity. The concept is simple, but the challenge was stabilising the RNA, which is inherently labile. This was done by encapsulating the RNA in a lipid (fat) nanoparticle. In human clinical trials, both these RNA vaccines showed excellent safety and efficacy, and are being used in multiple countries. Recent reports from the US show these vaccines also perform very well in real-life conditions.

Several Covid-19 vaccines are built using the common cold causing adenoviruses. A few adenovirus genes are taken out to curb its replication, and the spike gene from SARS-CoV-2 is introduced into this backbone. The modified adenovirus then works like a ‘Trojan horse’ to carry the spike gene into the cell, where it produces its RNA and in turn the spike protein. Examples of these ‘viral vector’ vaccines include those from Oxford-AstraZeneca (Covishield in India), Johnson & Johnson, Russia’s Gamaleya Institute and China’s CanSino Biologics.

Established platforms such as inactivated whole viruses and protein subunit vaccines have also been developed. The former includes vaccines from India’s Bharat Biotech (called Covaxin) and China’s Sinopharm and Sinovac. Vaccines from American Novavax and Russia’s Vector Institute are examples of the latter.

The clinical development of vaccines involves three stages of testing. In Phase 1, the vaccine is tested in typically 20 to 100 healthy volunteers to check if it is safe, if it gives rise to any serious side effects, and if the dose size is related to adverse effects. Phase 2 is carried out on several hundred volunteers to determine the most common short-term side effects, optimise the dose and schedule, and ask if the volunteers’ immune system responds to the vaccine. Phase 3 is done on hundreds or thousands of volunteers to test vaccine efficacy. These volunteers are divided equally and randomly into those who get the vaccine and those who don’t (the term is known as placebo) and then followed up to see how many develop the disease (or infection) over a predetermined period of time. This phase addresses how the vaccine and placebo groups compare, if the vaccine is effective, whether it is still safe in a large and more diverse volunteer pool, and what are the most common side effects. Since vaccines are administered to healthy people, safety is paramount and is tested in all three phases.

Efficacy remains a poorly understood term. It is calculated as 100x (1 minus the attack rate with vaccine divided by the attack rate with placebo). Let us look at the Pfizer/BioNTech vaccine Phase 3 data to understand this. In this trial, 43,661 volunteers were followed over a period of three months. During this time, 170 people developed the disease, of which 162 were in the placebo group and only eight were in the vaccine group. The calculated efficacy is 100 x (1-8/162), which equals 95 per cent.

But this does not mean that 5 per cent of the people who get the vaccine would develop Covid-19. Efficacy is a measurement of how much a vaccine lowers the risk of symptomatic Covid-19 disease. Efficacy also depends upon the details of the trial. The Novavax vaccine showed 90 per cent efficacy in the US, but only 49 per cent in South Africa—because in the latter case the trials were done at a time when a variant virus was predominant in that country. Efficacy is tested in a representative population under highly controlled conditions of a clinical trial, but the effectiveness changes when the vaccine moves out into the population. Finally, the efficacy value is time limited. The 95 per cent efficacy of the Pfizer/BioNTech vaccine is based on data over a period of three months. This would change over six months, one year or five years. The most important metric for the effectiveness of a Covid-19 vaccine is how well it protects against severe diseases and mortality. On this metric, all approved vaccines are 100 per cent effective. Therefore, it makes little sense to compare different vaccines based on their efficacy in clinical trials.

WHAT ARE EMERGING mutants or variant viruses, and are current vaccines effective against them? Mutation is natural and random. When a virus multiplies, its genome (RNA or DNA) also makes copies and errors are introduced during this process, much like the spelling errors we make while writing. While we can go back and correct those spelling mistakes, viruses, especially RNA viruses, cannot. Most mutations are detrimental to the virus and are never seen. The ones that circulate give some selective advantages to the virus, such as better infectivity, increased transmission or immune evasion. These mutations are selected, carried forward and accumulate into aviral lineage.

Two mutations are known to increase infectivity and evade antibodies. Another key mutation has been found in samples from Kerala, Andhra and Telangana. Also worrisome is that the UK variant is in 80 per cent of new cases from Punjab, which is another surge state

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The virus that emerged from Wuhan, China in December 2019 has changed significantly. A mutation called D614G that emerged sometime in late January 2020 allowed the virus to infect, replicate and transmit more efficiently. Consequently, this has now become the dominant strain, accounting for over 99 per cent of the virus circulating globally. Other more recent mutations have developed in this background. Scientists have discovered a few variants of concern (VOC) circulating in the world. These are called so because they either display better infectivity and spread or are partially able to evade vaccine-derived immunity. The most prominent ones include the following.

The UK variant—also called lineage B.1.1.7—containing 23 mutations, was first discovered in the south of England but is now found in 114 countries. The defining spike protein mutations in this lineage are N501Y and P681H, but more recent viruses of this lineage found in Britain and the US also carry the E484K mutation.

The South Africa variant—also called lineage B.1.351—contains nine mutations and is now reported from 68 countries. The defining spike protein mutations in this lineage are N501Y, E484K and K417N.

The Brazil variant—also called lineage P.1—contains 16 mutations and is now reported from 36 countries. The defining spike protein mutations in this lineage are N501Y, E484K and K417T.

Mutations are concentrated in all these VOCs in the spike protein, with the N501Y mutation being common to all three. That cannot be a coincidence. Rather, it suggests this mutation helps the virus. The spike protein binds to human cells to facilitate virus entry, which is required for the virus to multiply. The parts of the spike that do the binding are thus crucial to its success, and are the best possible targets for antibodies. Naturally, the goal of virus evolution would be a spike that binds better to the target and is harder for antibodies to neutralise. The mutations that have accumulated in the VOCs seem to do just that. N501Y makes binding tighter and E484K makes antibodies less effective.

These variants are a cause for concern but not worry for vaccination efforts. In a study of the Oxford-AstraZeneca vaccine published on March 30th, those infected with an E484K free B.1.1.7 lineage virus fared equally well compared to a non-B.1.1.7 virus, in terms of protection against the disease, but the efficacy was both a bit lower and more uncertain. Though antibodies from trial volunteers were less able to bind to B.1.1.7 lineage virus particles, vaccines stimulate more of the immune system than just antibodies. Both the Novavax and Johnson & Johnson vaccines are also effective against the UK variant, but show reduced efficacy against the South African and Brazil variants. India’s Covaxin also seems to neutralise the UK variant well in laboratory tests, but results are not yet available from the population or for other variants.

A concerted genome sequencing effort in India has brought together 10 national laboratories under the umbrella of the Indian SARS-CoV2 Consortium on Genomics (INSACOG). On March 24th, it revealed the detection of 771 VOCs among 10,787 virus genome sequences from infected Indians. These included 736 UK variants, 34 South African variants and one Brazil variant. Around 15 to 20 per cent of samples from Maharashtra, which is going through a big surge, show the emergence of a double mutant virus since December 2020. The two mutations—L452R and E484Q—are known to increase infectivity and evade antibodies. Another key mutation at the business end of the spike protein, called N440K, has been found in 6 to 50 per cent samples from Kerala, Andhra Pradesh and Telangana. Equally worrisome are reports that the more infectious UK variant is now seen in about 80 per cent of new cases from Punjab, which is another surge state.

“Vaccines do not save lives. Vaccinations save lives”, says Walter Orenstein, former Director of the United States Immunization Program at the Centers for Disease Control and Prevention. The world has a historic opportunity to end the pandemic using vaccines and vaccination. India has an important role to play. Let us not waste this opportunity.

About The Author

Shahid Jameel

Shahid Jameel is a virologist and Director of the Trivedi School of Biosciences, Ashoka University