The emergence of various variants of SARS-CoV-2, the virus that causes COVID-19, shows that it is the nature of viruses to mutate constantly. Cases of infection with these variants of the SARS-CoV-2 around the world are increasing like in the United Kingdom (UK), Brazil, and South Africa. These variants are known as variants of interest (VoIs). As of March 2, 2021, about 106 countries have reported cases of variants. So, the vaccines made to prevent the spread of COVID-19 should have the capability to adapt to the varying mutations if they are to remain effective against them. The notion is that vaccines that bring out higher immunogenicity (the ability of a foreign substance to enter a person’s body and cause an immune response) would have higher efficacy. These understandings are very crucial as countries are striving hard and prioritising different vaccines to get rid of COVID-19.
Types of Vaccines
There are many vaccine candidates and many are in the pipeline for COVID-19. Based on technicalities of development, they are of four types—those which use whole virus; protein subunit; nucleic acid (RNA and DNA); and viral vector. As of January 20, 2021, about 15 candidates of vaccine against COVID-19 have been developed, including BNT16262/COMIRNATY by Pfizer and BioNTech; AZD1222 by Oxford; mRNA-1273 by Moderna; and ChAdOx1 nCoV-19 (Covishield) by India.
At present, there are a number of vaccines for SARS-CoV-2 infection. Most of them use a recombinant spike glycoprotein, which is either mRNA-based as in the Moderna and Pfizer-BioNTech vaccine; via an adenovirus vector (engineered viruses made to carry a gene from SARS CoV-2 into human body so that cells read it and make coronavirus spike protein) as in the Oxford-AstraZeneca vaccine; or via injection of the protein itself as in Novavax vaccine.
Many viral vaccines work by presenting the entire virus in a live attenuated form (measles, mumps, rubella, rotavirus, and some influenza vaccines) or an inactivated form (hepatitis, Salk poliovirus, rabies, and some other influenza vaccines). This leads to a polyclonal response (involving several different immune cells) to a number of viral proteins. Due to this multiplicity of humoral and T cell response) (relating to immune response), no convincing vaccine escape strains have been documented for these viruses. But in case of influenza virus, which is an RNA virus, the immune response to previous influenza strains (or vaccines) is no longer effective in preventing infection by the new strains.
In case of SARS-CoV-2, which is a unique strain of RNA viruses, the rate of mutation is lower than that of other RNA viruses and it is also non-segmented. SARS-CoV-2 mutates slowly, accumulating around two single-letter mutations per month in its genome. This rate of change is about half that of flu viruses. Though relatively low mutation rate of SARS-CoV-2 offers some protection, prolonged infection in immunocompromised hosts might accelerate mutation. Various findings suggest that variants of SARS-CoV-2 could evolve with resistance to immunity induced by recombinant spike protein vaccines which are based on the original sequence, i.e., Wuhan-Hu-1.
Three Main Variants of Interest
As per the World Health Organization, a SARS-CoV-2 isolate is a VoI if:
(i) it is phenotypically changed, i.e., it has a different structure and properties compared to a reference isolate, or has a genome with mutations that lead to amino acid changes associated with phenotypic implications; and
(ii) it has been known to cause community transmission/multiple Covid-19 cases or has been detected in multiple countries.
Three types of phenotypic changes appear to be associated with a VoI, which include increase in transmissibility or detrimental change in COVID-19 epidemiology; increase in virulence or change in clinical disease presentation; decrease in the effectiveness of available vaccines and treatment. In all three variants, there are changes in the spike protein.
UK Variant UK variant is known as B.1.1.7 or VoC 202012/01. It was first detected in the UK in December 2020. There are multiple mutations in the spike protein of this variant, which have resulted in the virus becoming about 50 per cent more infectious and spreading more easily.
South Africa Variant It was detected in South Africa in October 2020 and is called 501Y.V2 or B1.351 VOC202012/02. There are nine changes in the spike protein of this virus in comparison to the reference—the ‘Wuhan-1 D614G spike mutant’ that was previously prevalent in South Africa. It is also a highly contagious variant. The concerns about this variant are that the spike mutations could lead to antigenic changes that are detrimental to monoclonal antibody (antibodies made using identical immune cells) therapies and vaccine protection.
Brazil Variant This is called P.1, a branch of the B.1.1.28 lineage. It was first reported by the National Institute of Infectious Diseases in Japan in four travellers from Brazil.
It shares some mutations with the South Africa variant like E484K and NS01Y. As per the US Centers for Disease Control and Prevention (CDC), some of the mutations in this variant may affect its transmissibility or the abilities of antibodies generated through previous infection or through vaccination to neutralise the virus.
The mutation E484k is of prime concern to the scientists. This mutation was found in the South Africa variant (B.1.351) and the Brazilian variant (P.1) Later on, it was also found in the UK variant. The emergence of this mutation raised apprehensions over the efficacy of the approved vaccinations.
Receptor-binding Domain
A receptor-binding domain (RBD) is a main part of a virus which is located on its ‘spike’ domain that allows it to dock to body receptors to gain entry into cells and result in infection. These are also the key targets in the prevention and treatment of viral infections.
While there is a need to monitor all mutations found in emerging variants of coronavirus, mutations occurring in the spike protein of virus, specifically the RBD section of the spike protein, are of particular interest to scientists.
Mutations in the RBD can help the virus bind more tightly to the cells of the body, making it more infectious.
The immunity we develop to the coronavirus, following vaccination or infection, is largely due to the development of antibodies that bind the RBD. Mutations in this region can allow the virus to, sometimes, evade these antibodies. This is the reason why E484K is called ‘escape mutation’.
The name of the mutation comes from the position in the string of RNA (the genetic code of the virus) where it occurs (484). The letter E refers to the amino (glutamic) acid that was originally at this location. The letter K refers to the amino (lysine) acid that was replaced in the location.
Several studies have shown that mutation E484K stops antibodies that target this position from binding to it. However, after an infection or vaccination, humans do not produce antibodies, targeting only one area of the virus. Human body produces a mixture of antibodies, each of which targets different areas of the virus. How detrimental it is to lose the effect of antibodies targeting this one specific region will depend on how much the immune system of a person relies on antibodies targeting this particular site.
Studies have also shown that while the effectiveness of the vaccine to provide protection against variants carrying the E484K mutation was slightly reduced for some people, it was still within an acceptable level.
Clinical trials can show whether vaccinated individuals recognise SARS-CoV-2 variants differently. It would also make it clear whether mutations decrease vaccine protection in some vaccinated individuals. As most of the vaccines currently available are based on a recombinant spike protein sequence, the vaccines should be periodically reformulated if there appears any evidence that particular variants influence vaccine efficacy. This way vaccines would effectively match the circulating strains.
Thus, the overall effectiveness of the immunisation would be correlated with rates of vaccine uptake. The higher the proportion of a population vaccinated, the lower would be the number of susceptible individuals. This would result in fewer opportunities for SARS-CoV-2 to spread and mutate.
Results of Clinical Trial of Vaccines
The clinical trials of Covaxin and Covishield showed that irrespective of the SARS-CoV-2 strain, roughly the same amount of antibodies were needed to neutralise the virus. This implies that Covaxin-generated antibodies were as effective against the mutant UK variant as the virus used in order to develop the vaccine. Tests conducted by Pfizer and Moderna also had similar results.
The study showed that Covaxin is a promising candidate and can be used in larger trials. The main limitation of Covaxin trials was that it did not take into consideration South Africa variant (E484K) (which was essential).
Novavax, after its initial clinical trials for the older variant of SARS-CoV-2, had stated that its dose was 96 per cent effective in preventing the disease. However, the efficacy dropped to 60 per cent in a small trial in South Africa where B1.351 accounted for most infections.
Johnson & Johnson’s Janssen dose was 72 per cent effective for the older variant when trials were conducted in the USA. The efficacy rate dropped to 57 per cent for the new South Africa strain B1.351.
Moderna, too, reported that there was a drop in the efficacy of the vaccine against South African variant.
AstraZeneca Oxford vaccine AZD1222 (SK Bio) also showed lower efficacy rates to the South Africa variant B1.351.
Artificial Intelligence (AI) to Speed-up Vaccine Development
The research team from the Viterbi School of Engineering under the University of Southern California (USC) has developed an Artificial Intelligence (AI) method to speed up the analysis of vaccines and determine the best potential preventive medical therapy for SARS-CoV-2 mutations. This new method is expected to counter emergent mutation of SARS-CoV-2 and speed up the vaccine development in order to stop the spread of the virus.
Researchers say that this AI framework, once applied to the specifics of this virus, would be able to provide the vaccine candidates in a few seconds. They can then move them to clinical trials quickly to achieve preventive medical therapies without compromising safety. This method would help to stay ahead of SARS-CoV-2 as it mutates around the world. The study says that when this method was applied to SARS-CoV-2 virus, the computer model quickly eliminated 95 per cent of the compounds that could have possibly treated the pathogen. It also identified the best possible vaccine candidate.
The AI-assisted method predicted 26 potential vaccine candidates that would work against SARS-CoV-2 virus. During the study, the scientists identified the best 11 vaccine candidates to construct a multi-epitope vaccine. Such a multi-epitope vaccine could attack the spike proteins that the SARS-CoV-2 uses to bind and penetrate a host cell. The vaccines could be designed in such a way that they focus on the epitope (portion of antigen which is capable of stimulating an immune response) of the contagion. This process would prevent the spike protein functioning. This would counteract the ability of the virus to replicate further.
Multi-epitope Vaccines are constructed by multiple virus protein fragments which are rich in overlapping epitopes. They consist of the vital part of the virus and reduce unwanted components capable of triggering adverse effects. These types of vaccines are powerful for fighting viral infections and provide excellent vaccine candidates for clinical trials.
This method, if successful, could be useful during this stage of the pandemic when the virus is mutating in populations around the world. The researchers are of the opinion that even if SARS-CoV-2 becomes uncontrollable with the current vaccines, or if new vaccines are needed to deal with new mutations, this USC’s AI-assisted method could be used to design other preventive mechanisms quickly.
Presently, in its research study, the USC scientists have used only one B-cell epitope and one T-cell epitope. Once a bigger data set is applied, then more combinations and more comprehensive and quicker vaccine design tools could be developed. The scientists expect that this method could perform accurate predictions with over 7,00,000 different proteins in the dataset.
The raw data for this AI-based research was obtained from a giant bioinformatics database, called, Immune Epitope Database (IEDB). IEDB is the place where scientists around the world have been compiling data about SARS-CoV-2.
Conclusion
The changing mutations of SARS-CoV-2 have highlighted the importance of examining the combined effect of multiple mutations as opposed to studying only individual ones. It is unlikely that any single mutation would lead to complete escape from natural or vaccine-derived immunity. Regular modification of vaccines is very important. For example, the flu virus that causes seasonal influenza is itself highly adaptive, and that is the reason for the modification of its vaccine every year. Accordingly, annual vaccination is also necessary. If SARS-CoV-2 behaves similarly, then periodic adaptation of vaccines to ever-emerging viral variants will be required. If the research on the AI-based tool is successful, it will help the world stay ahead of the SARS-CoV-2 mutations.
© Spectrum Books Pvt. Ltd.