Covid-19 mutations call for new vaccine design, careful inoculation strategy

By Ameen Kamal is the Head of Science & Technology at EMIR Research,

By now, most of us would have seen graphical representations of the Covid-19 virus depicting a spherical structure with many protruding ‘spikes’. This is the part of the virus that enables it to attach to our cells and enter it – causing infection. As such, it has become a popular target for vaccine developers.

The problem is that these protruding structures are also relatively less stable i.e.  more susceptible to changes through genetic mutation. We are now seeing more reports on these new Covid-19 virus variants with notable spike mutations and there are concerns that our immune system will not recognise it if these spikes change significantly enough – rendering current versions of vaccines ineffective.

Although recent reports of studies conducted by some vaccine makers claim current vaccines to likely be effective against these new Covid-19 variants, it may only be a matter of time before significant mutations emerge to a degree requiring the need for continuously updated versions of the vaccines (to keep up with the mutation).

Mutations will keep on happening and may result in a situation akin to the annually-needed common flu jabs. With the way things are looking, it doesn’t look like this would be a one-off affair.

But why go through this route when there could be other parts of the virus that are less susceptible to mutational changes and can also trigger an immune response?

According to clinical research fellow in viral immunology and veterinary surgeon from the University of Cambridge, Sarah Caddy, our immune system recognises other parts of the virus too (albeit at varying degrees) and the overall structure of the Covid-19 virus is not only the spike (which is made up of “S” proteins) but also consists of “E” proteins making the envelope, “M” proteins making up the membranes and “N” proteins making up the nucleocapsid (proteins inside the virus associated with the viral genome).

Furthermore, Caddy referenced a research article by McEwan and James in the Progress in Molecular Biology and Translational Science journal, which pointed that after a Covid-19 virus infection, the human body actually produces N protein antibodies the most and not spike protein antibodies. This is a strong indicator that another immunity mechanism could be utilised in vaccine design.

The related mechanism was elucidated by Caddy and other researchers from MRC Laboratory of Molecular Biology and LMB’s Biological Services Group in Cambridge when they discovered that N proteins from viruses that have made its way inside human cells are destroyed through the action of TRIM21 (a protein inside cells), triggering subsequent immune response to destroy infected cells.

The point here is that N proteins (and potentially other parts of the virus) also has the potential to become a vaccine target and not just the mutation-prone spikes. On this matter, Caddy pointed on the low mutation rates of the N protein sequence, relative to the spikes. This opens up potential vaccine design target that is more stable and could be longer-lasting before needing an updated version.

Thus, to ensure a broader target which are less susceptible to mutations, future vaccine designs should consider coding for targets that are less susceptible to mutational changes, or perhaps explore a combination of spike codes as well as N codes (or other parts of the virus that are less prone to significant mutations) to provide a potentially longer-lasting immunity, as per the findings by the team at Cambridge.

All the leading vaccines right now such as the mRNA-based vaccines from Pfizer/BioNTech, Moderna, and AstraZeneca/Oxford as well as adenovirus vector type from Russia’s Gamaleya Research Institute code for information that allows our cells to produce viral spikes or proteins that form the spikes.

With the various vaccine options under the consideration of the Malaysian government, combined with uncertainties surrounding virus mutation (particularly with vaccines that focus on the spikes only) and its impact of vaccine validity/effectiveness, duration of immunity retainment and potential long-term effects, the authorities may consider the following:

• Ensure procurement deals include favourable provisions on effectiveness, safety, immunity retainment, validity of the procured vaccine versions and stagger purchase commitments with related milestones.
• Conduct ‘pilot-run’ of vaccine roll-out using several types of vaccines. The pilot run should target smaller populations first but it’s necessary to familiarise with logistics and handling.
• Larger-scale of a ‘first-batch’ vaccination roll-out using involving different types of vaccines, taking lessons learn from the pilot stage. This first batch roll-out may also be considered a phase to funnel future vaccine choices.
• Monitor the first batch roll-out similar to a late-stage clinical trial. Results from the third phase of clinical trials from the leading vaccines mentioned earlier have shown to be promising. However, without a significantly longer-term study (especially on Malaysian demographics), potential long-term effects, immunity retainment and potential impact of virus mutations cannot be determined with better certainty.
• Authorities must ensure it is ready to track, monitor, gather and analyse this ‘big data’. This must not be overlooked or underestimated. Given the overwhelmed healthcare infrastructure and highly occupied medical professionals and health workers, authorities must plan and execute this accordingly. If not, it would be a waste of valuable and potentially life-saving data.
• Monitoring viral genome sequence to detect mutations and correlate medical data from the first batch of vaccine roll-out.

Instead of petty and selfish power squabbles, politicians should focus on the above. The rakyat and the economy depends on it. Furthermore, the above recommendations may allow Malaysian authorities better visibility to pursue a data-driven decision-making to potentially narrow down its best option for the next batch – if and when deemed necessary.

Mutations of the spike are not surprising given that it is the part of the virus that is closely linked to its survival. The better it can attach and enter cells, the higher the chances of its survival. Keeping it’s host alive would also be beneficial. Observations on recently discovered mutated Covid-19 strains appear to support this notion.

In December last year, The New York Times reported new strains of the virus detected in the U.K. and South Africa which were reported to be 70% more contagious than other variants. According to the Centers for Disease Control and Prevention (CDC), the U.K strain is known as lineage B.1.1.7 while the one from South Africa is lineage B.1.351. Both strains have notable mutations in the spikes.

The CDC reported that based on “preliminary epidemiologic indicators” the B.1.1.7 variant is linked with “increased transmissibility”, but so far it doesn’t seem to impact disease severity or vaccine efficacy. More data is needed but the currently observed increase in infectivity (but not severity/lethality) is in line with the ‘reasonable’ mutational trajectory postulated earlier.

In October last year, EMIR Research article highlighted how Covid-19 virus mutation may pose a risk to the future effectiveness of Covid-19 vaccines and the potential scenario of needing additional batches of the same vaccine-type due to low immunity retainment and/or updated batches of vaccines faster than expected (vaccine validity) due to virus mutations.