Vaccines and the coming third Covid-19 wave

India’s, and the world’s, best bet is to accelerate vaccination, and to do so with inactivated whole virion vaccines to the extent possible

If you trace the history of pandemics, their natural course tends to have three waves. During the first wave, the aged and those with weak immune systems (immune-compromised individuals) are the worst hit; in them, the virus learns to circumvent the human body’s immunity. The young and those with strong immune systems— the immune-uncompromised subset of the population— remain mostly asymptomatic or show mild symptoms, thus becoming the main, yet unnoticeable, spreaders of the virus. In the absence of severe disease, the younger population mounts only a sub-optimal (i.e., incomplete) immune defence against the virus. On a community level, this creates only a ‘sub-optimal immune pressure’, which facilitates the selective propagation of viral mutants that have acquired increased infectivity to circumvent and escape the immune lines of defence. Several such mutants of the Covid-19 virus have already been reported. Let’s call these ‘escape mutants.’

The aged and immune-compromised individuals who recover from Covid-19 disease develop natural antibodies and a memory-based immune response which protects them against disease in the second wave of the pandemic. However, due to the incomplete defence elicited in the first wave among the younger and immune-uncompromised subset of the population, this subset succumbs to disease in the second wave, which is what we are seeing currently.

Read | Seeking a pill to cure Covid-19: Drugmakers eye alternative to vaccines

Come the third wave, the natural antibodies gained through recovery in the first wave among the aged and immune-compromised individuals will have waned or started to wane. Their capacity to recall immune memory is slower. Therefore, the balance will tilt once again to cause greater rates of infection in them. At this point, however, by virtue of having gained a robust memory-based immunity (during the second wave) which they can recall quickly, the younger and immune-uncompromised individuals will create an optimal immune pressure, popularly termed ‘natural herd immunity’, to stop further transmission of the viral mutants. This, however, occurs in the absence of human interventions such as mass vaccination.

Mass vaccination campaigns disrupt the natural course of the pandemic and make it less predictable. Uneven and slow-paced mass vaccination perpetuates 'sub-optimal pressure' at the community level, which allows repeated exposure of the virus to vaccinal antibodies, allowing it to evolve vaccine-resistant mutants. This may pave the way for a fourth wave in which the vaccinated subset of the population will be the asymptomatic spreaders of the virus while unvaccinated individuals may succumb to severe disease; and potentially a fifth wave in which even the vaccinated population is affected by the vaccine-resistant mutants.

However, I’m not here making a case for allowing the pandemic to run a natural course. That is not an option for modern democratic governments faced with millions of infected people, healthcare systems and hospitals crumbling, and hundreds of thousands of deaths. Nor can we now allow viral mutants from other countries that have mass-vaccinated to make their way into India. Our best bet to break this cycle of pandemic waves therefore is to expedite universal vaccine coverage with the ‘best’ vaccines available.

Currently, a milieu of prophylactic (i.e., preventive) vaccines are being administered globally (including Covishield, Sputnik V, Moderna’s mRNA-1273 vaccine, Pfizer-BioNTech’s Comirnaty, and the soon-to-come ZyCoV-D of Zydus Cadilla), which are all ‘spike protein-based vaccines’— while they differ in the technology of vaccine development and delivery, all of them uniformly introduce into the human body and elicit immunity only against a protein sub-unit (i.e., the spike protein) of the coronavirus, as opposed to helping develop immunity against the whole virus. So, as the virus introduces mutations in its spike proteins, the efficacy of these vaccines to protect against disease will begin to diminish. The Oxford Covid-19 Vaccine Trial Group has already published evidence-based studies that reveal the reduced effectiveness of Covishield against viral strains with mutated spike proteins. Similar studies have demonstrated the reduced effectiveness of Sputnik V, too, against mutants.

The reduced effectiveness is likely because the vaccinal antibodies bind to the mutated spike protein with reduced or poor capacity to neutralise the mutant. It is suspected that the overwhelming presence of the vaccinal spike protein-specific antibodies may also out-compete the natural antibodies of our immune system from binding to the viral mutant, thereby lowering our natural defence mechanisms. In-depth studies are required to address such concerns. What’s noteworthy, however, is a 2015 study by Andrew Read, et al., in animal models that showed that ineffective (or ‘leaky’) vaccines can facilitate the evolution of mutants that put unvaccinated populations at greater risk of severe disease. While Moderna and Pfizer vaccines have proven effective against the current spontaneously occurring ‘escape mutants’, they will lose their ability to provide immunity against the vaccine-resistant mutants that would emerge in the near future.

In countries like the UK and Israel, mass vaccination with spike protein-based vaccines has ushered in a ‘transient herd immunity.’ While the severity of the disease is temporarily addressed, the transmission of the virus is not halted – the repeated exposure of the virus to the overwhelming presence of spike protein-specific antibodies in the vaccinated population facilitates the propagation of vaccine-resistant mutants which, in time, could become fully resistant to these vaccines. The transient herd immunity will shatter.

In a populous country like India, as a slow-paced vaccination occurs in the backdrop of high infection rates and severe disease, the transmission of the virus is accelerated. This accelerated viral transmission in a population that offers an inadequate immune-pressure, may in turn accelerate the emergence and propagation of vaccine-resistant viral mutants. It’s time, therefore, to shed our myopic view, and adopt a vaccination policy that is beneficial not just to the individual but to the population as a whole.

The best vaccines are those that mount immunity closely similar to the one our body naturally acquires, and mimic a natural setting required to shift the balance toward acquiring herd immunity. The most effective in this regard is a live attenuated vaccine, i.e., vaccines that administer weakened strains of the disease-causing virus. These come with the danger of causing infections/disease to varying extent in individuals given such a vaccine. An example is the potential vaccine candidate under evaluation in animal models at Japan’s Osaka University. Such vaccines are currently unavailable in the market. They are, in any case, not suitable for the Indian context of paucity of healthcare services and administrative chaos.

The next best option is the inactivated whole virion vaccine, i.e., a vaccine that administers ‘dead’ virus that cannot cause disease or transmit it but allows the immune system to develop holistic immunity against the entire virus, not just its spike protein or parts of it. Such a vaccine is available in India – Covaxin. While initially shrouded in controversies, the emerging data on this vaccine looks promising. Studies have proven its effectiveness against emerging mutants. Unlike sub-unit vaccines that only tend to clear the viral load in the respiratory system, the inactivated whole virion vaccine additionally clears the viral load from extrapulmonary organs such as the gastrointestinal tract, urinary bladder and skin.

Though live-attenuated and inactivated whole virion vaccines too are prophylactic in nature and their efficacy in individuals slightly lower than that of spike protein-based vaccines, they elicit a holistic immune response that does not create any selective immune-pressure (as in the case of spike protein-based vaccines) that favours viral mutation, and therefore they will not become ineffective in time. In other words, while spike protein-based vaccines protect individuals well – and therefore individuals should not hesitate to get vaccinated with these -- whole virion vaccines protect both the individual and benefit the wider population by slowing down mutation and transmission of the virus. And that’s a consideration for policymakers at the highest levels to ponder over and act on.

So, here is what the government and our vaccine-makers should do to brace ourselves for a third wave:

1. First, publish the results of the Phase III trial on Covaxin/other vaccines based on similar technology at the earliest and clear up doubts and controversies. Obtain WHO approval for Covaxin speedily. Building trust is essential.

2. Ramp up manufacturing capacity of vaccines, especially of inactivated whole virion vaccines.

3. Revise vaccine procurement and distribution process to ensure equitable access and vaccination for all. Uneven vaccination allows the virus to evolve increasingly potent mutants.

4. Conduct a well-designed study on the safety and efficacy of administering a booster shot of an inactivated whole virion vaccine following an earlier immunisation with spike protein-based vaccines.

5. Focus research efforts on developing therapeutic vaccines that can fight/cure disease in hospitalised patients, alongside improving the window of protection offered by prophylactic vaccines.

(The writer is an independent researcher and former senior science adviser to the UK government)