KUALA LUMPUR: A high degree of infection means high levels of virus multiplications, leading to higher chances of random mutations. The more intense the spread, the higher the chances (and accumulation) of mutations and the higher the chance for the emergence of variants.

It’s likely a major contributing reason to why places with very widespread infections, such as Brazil, India, and the UK, have recorded first cases of a certain variant. Nevertheless, these experiences provide a hint that stopping infections and transmission is the key to addressing this issue significantly.

Specifically, next-generation of vaccines should be: 1) reducing variant evasion of the immune system and 2) eliciting both systemic immunity AND mucosal immunity in order to stop the virus at the routes of transmission, in addition to protecting against severe symptoms.

This would reduce the number of viruses in circulation, and therefore, reduce the chance of mutations. We can’t be in a total lockdown forever, and viruses will do what viruses do best when humans start to mingle. So, it’s the vaccines that have to change.

Current vaccines are good at preventing severe disease, and there is increasing evidence that vaccination helps reduce transmission. But it does not appear to completely stop someone from carrying it, being infected with, and transmitting it.

Current vaccines are injected therapies (e.g., intramuscular routes) and are generally good at eliciting systemic immunity. The types of antibodies and the immune cells it triggers may travel throughout the body defending against invaders, but getting to the mucosal lining (protective mucous that cover surfaces of lungs, nasal area, gastrointestinal surface etc.) has been reported to be inefficient.

This is important because the mucosal surfaces of our respiratory system are not only where infection first starts to happen, but it’s also the place where virus is transmitted (droplets from the respiratory system discharged through the nose and mouth). Thus, stopping infection in these places (such as epithelial cells in the lungs and nasal cavities) would mean stopping someone carrying and transmitting the virus - effectively stopping further spread and circulation of the virus which stops further chances of random mutations.

Mucosal vaccines have been reported - subject to their designs such as target antigens, adjuvants, delivery routes - to induce both systemic and mucosal immunity. Effective mucosal vaccines are also needed to trigger production of secretory immunoglobulin A (secretory-IgA), which is a type of antibody unique to mucosal areas that helps fend off infections. Unlike typical jabs, mucosal vaccines can be delivered through the nose to get vaccines to the nasal cavities and the respiratory tract.

Without mucosal immunity, viruses may still be lurking in the respiratory cavities, infecting cells there, multiplying, shedding and therefore, continue to be transmitted - even in vaccinated populations with systemic immunity. Following this scenario, a systemically-vaccinated population may still be generally protected from severe symptoms and although transmission (and mutation) may be slowed down, it could be only a matter of time before a significant mutation emerges to cause immunity breakthrough.

This could be what we are observing with the Delta variant, whereby it may be driving cases around the world, even in populations with a high percentage of vaccinated individuals. Thus, it’s likely that variant spread in populations that are not protected or have low percentage of vaccinated population would have a rise in cases as well increase in severe cases and death.

As it is right now, variant Delta won’t be the last of its kind. Stopping transmission is key, and mucosal vaccines may be the next arsenal, if not an addition to current tools. Non-vaccine interventions such as drugs and chemicals must also be considered.

Additionally, next-gen vaccine design has to address variant evasion of immunity. Updating vaccines and booster shots appear to be the current response to this situation, but it could be a very risky assumption to think that we can always update vaccines in time (and get it to the rest of the world) and win the race against the speed of transmission and rate of mutations. A profitable situation for vaccine developers, but with potentially serious consequences for the rest of the world.

We have gone through a handful of Greek alphabets in the span of over a year with emerging variants obtaining significant increases in transmissibility, while vaccines have struggled to be disseminated globally. Unless there is a significant increase in capacity, it will take time to produce billions of new updated vaccines doses and it would face similar logistics and production hurdles. Thus, betting on updated vaccines or boosters as the only solution in some form of future “normalcy” may be a risky choice.

Furthermore, the protection from updated vaccines or boosters should ideally provide protection simultaneously, or at least, within a very close timeframe worldwide. Other parts of the world that continue to have widespread infections for an extended time would have higher chances for variant emergence, breaching into other corners of the globe and the cycle continues. Therefore, vaccine warfare and inequitable vaccine access may have contributed to the rise in variants as well.

One potential vaccine design strategy to increase the level of protection against variants is that the antigen target may have to be diversified. The well-known “S” or “spike” protein is a good choice in vaccine design given its key role in cell entry, but perhaps other targets should be included in the vaccine.

Virus spikes are essential to its survival and therefore, the most prone to mutations. Expectedly, variants of concern tend to have notable mutations in the spike, resulting in structural changes (physical and chemical properties) of the spike making it “unrecognisable” by the immune system, effectively “evading” antibodies that target these spikes.

In EMIR Research article “COVID-19 mutations call for new vaccine design, careful inoculation strategy” published in January this year, we pointed to a research where “N” proteins (in addition to “S”, or spike proteins) could be a viable target.

This could be a reasonable sequence of protection in the sense that if the spike fails, and the virus manages to get into a cell, other parts or fragments of the virus (such as the N protein) may be exhibited by the infected cells that could be recognised by other immune actors such as T cells. Unlike the S protein, the gene sequence for the N protein has been reported to be more conserved.

An article in The Atlantic published in late May this year pointed to how an immunologist at MIT shares the view that a vaccine that includes both N and S targets could be a good idea as far as preparing multiple layers of protection goes.  However, the MIT immunologist also pointed out how having too many targets may produce too many antigen proteins that shift away immune resources from sufficiently dealing with the spikes. So, balance is key.

Antigen targets could vary but the point here is that without interventions that achieve the objectives of stopping or significantly suppressing transmission (in addition to protection from serious symptoms) and a wider coverage against variants, we may lose the race in this reactive “cat and mouse” game against variants sooner than we think.

There are developers exploring such vaccine technologies with similar approaches but there appears to be relatively few compared to other vaccine candidates in development, and most appear to be in early clinical trial phases. Bigger corporations should embark on accelerating these developments, and not stop at the level of perpetually updating vaccine versions.

Theoretically, even though waning immunity retainment may still require boosters, next-gen vaccines with the mentioned characteristics may cover wider range of potential variants, extending vaccine validity before needing new versions. Combining this with mucosal immunity which supresses infection and transmission, virus circulation is inhibited, and the cumulative impact supresses mutations. Next-gen vaccines as mentioned here can provide hope for a sustainable form of future normalcy, and a “way-out” of the pandemic.

The future looks promising with talks of potential “universal” corona virus vaccines, but next-gen vaccines as described should provide significant edge against the virus, and we need it now. Current vaccines were developed at unprecedented speed and the same level of effort is needed for the next-gen of vaccines.




Ameen Kamal is the Head of Science & Technology at EMIR Research, an independent think tank focused on strategic policy recommendations based on rigorous research.

** The views and opinions expressed in this article are those of the author(s) and do not necessarily reflect the position of Astro AWANI.