COVID-19 vaccines vs new variants: Are we protected?

While more and more COVID-19 vaccines are getting rolled out globally, the world is also seeing new variants of SARS-CoV-2 emerging. How effective will the vaccines work against these new variants is largely unknown. Billions worldwide are watching closely and bracing themselves on how this might unfold.    

Already, the South Africa B.1.351 strain — the latest variant of concern — showed signs of abating the protection conferred by several vaccines, including the ChAdOx1 nCoV-19, NVX-CoV2373, and Ad26COV2.S vaccines, based on trial data from South Africa. 

Meanwhile, health experts are not resting on their laurels either. Researchers worldwide have been actively sequencing genomes of new variants and adapting these to upcoming vaccine designs.

It’s a race between vaccines and variants — an ongoing one at that. 

Rise of the mutants

Being an mRNA-based virus, SARS-CoV-2 easily mutates with each replication cycle. Of particular concern are those that have evolved to become more infectious and/or lethal than the one that started the pandemic.

One way this could happen (and has already happened) is through mutations in the sequence encoding the viral spike (S)-protein — which mediates its entry into the human cells.

As such, COVID-19 vaccines are designed to induce neutralizing antibodies (NAbs) that target the viral S-protein. These NAbs bind to sites within or near the receptor-binding domain (RBD) of the S-protein, thereby preventing SARS-CoV-2 from attaching to the ACE2 receptor and entering the host cell.     

Theoretically, mutations in the S-protein may impair NAb binding sites, leading to the vaccine's efficacy being compromised — in addition to promoting the virus entry into human cells and increasing its transmission.

The first major shift in the viral features took place around March-April last year, with the rampant spread of the D614G variant across the world. This variant, carrying a mutation in its S-protein, can replicate and spread more rapidly than the original wild-type virus. [Science 2020;370:1464-1468]

“Although this variant did not escape recognition by NAbs, it was a warning of what could happen,” pointed out Professors John Moore and Paul Offit from Cornell University, New York, New York and the University of Pennsylvania, Philadelphia, US, respectively, in an opinion column. [JAMA 2021;doi:10.1001/jama.2021.1114]

New variants: Faster and deadlier?

In August 2020, another variant with a mutation in the S-protein, dubbed the “UK strain” (or B.1.1.7 strain) began spreading in the UK and beyond. Armed with a key mutation — N501Y — in the S-protein, this strain spreads approximately 50 percent more rapidly than the current strains and is predicted to be the dominant strain circulating in the US by March 2021. [MMWR Morb Mortal Wkly Rep 2021;70:95-99]

Although being more infectious does not necessarily translate to increased lethality, there are studies suggesting that the B.1.1.7 variant caused more severe COVID-19 illness than nonvariants of concern.

In a preliminary report by the NERVTAG* from the British government, current evidence indicates that B.1.1.7 is associated with 30–70 percent increased risk of hospitalization and death than nonvariants of concern; although the panel also acknowledged that these are inconclusive thus far and that “data will accrue in the coming weeks, at which time the analyses will become more definitive.”

A silver lining, though, comes from preliminary data suggesting that the N501Y mutation did not appear to compromise vaccine efficacy against SARS-CoV-2. Serum samples from recipients of mRNA vaccines held up well against N501Y-containing variants, as was with nonvariants. [bioRxiv(Preprint) 2021;doi:10.1101/2021.01.07.425740; bioRxiv(Preprint) 2021;doi:10.1101/2021.01.25.427948]

Vaccines vs variants

A more worrying development, however, is the emergence of another N501Y-containing variant, first discovered in South Africa late last year. This new variant, known as B.1.351 (or N501Y.V2), harbours more mutations of concern in addition to N501Y, especially at sites in or near the RBD of the S-protein — at E484K and K417N.

While the site of the N501Y mutation in the UK strain, fortunately, is unlikely to affect the neutralizing efficacy of vaccines, the same cannot be assumed for the South Africa B.1.351 strain. The two key mutations of concern — E484K and K417N — in the B.1.351 strain, enable the virus to escape recognition by NAbs, which may render vaccines less effective against the virus.

An NIH** study showed that the mRNA-1273 vaccine was sixfold less active at neutralizing pseudovirion of the B.1.351 strain. Similarly, preliminary data suggest that sera from recipients of mRNA vaccines worked well against pseudovirion of the B.1.1.7 strain but to a lesser extent for the B.1.351 strain. [bioRxiv(Preprint) 2021;doi:10.1101/2021.01.25.427948; bioRxiv(Preprint) 2021;doi:10.1101/2021.01.15.426911]

In the real-world setting, early trial results demonstrated that the ChAdOx1 nCoV-19 vaccine was 74 percent effective against COVID-19 in the UK, but this figure dropped to 22 percent in South Africa, where the B.1.351 strain predominates. [Science 2021;doi:10.1126/science.abg9559]

While the NVX-CoV2373 and Ad26COV2.S vaccines fared better in South Africa, the efficacy for both was also lower compared with their activity elsewhere (for NVX-CoV2373: 89 percent vs 49 percent in the UK vs South Africa; for Ad26COV2.S: 72 percent vs 57 percent in the US vs South Africa). [Science 2021;doi:10.1126/science.abg8101; Science 2021;doi:10.1126/science.abg7115]

The virus, on the other hand, has not stopped evolving. The P.1 variant (or 501Y.V3) — a close relative to B.1.351 — has now been identified in Brazil. In the US, another lineage known as CAL.20C, which harbours the L452Y mutation, not unlike that of N501Y in the RBD, has popped out independently in southern California. What these changes behold for COVID-19 vaccines remains to be determined. [medRxiv(Preprint) 2021;doi:10.1101/2021.01.18.2124978]

The tipping point?

Amidst the growing threat of variants, experts believed that the currently available COVID-19 vaccines are still protective, at least for now — albeit to a lesser extent against the South Africa B.1.351 (ie, N501Y.V2) strain.

“The mRNA vaccines, in particular, induce such a strong NAb response that there could be enough ‘spare capacity’ to deal with reductions in the sensitivity of the variant to NAbs,” explained Moore and Offit. “In other words, N501Y.V2 [and the related virus from Brazil] may be less sensitive to NAbs, but not to an extent that will cause widespread vaccine failure.”

“Will the increasing dominance of N501Y.V2 in [South Africa] affect how well these vaccines protect the trial participants? Time will tell,” they added.

However, vaccines that induce lower levels of NAbs will have less “spare capacity” and may therefore be less effective, the experts pointed out.

Not only does the relentless evolution of the virus hold implications for vaccine-induced immunity, antibodies-based treatments are not spared as well. 

Already, the virus has evolved to become less susceptible to therapies based on neutralizing monoclonal antibodies and convalescent plasma. The B.1.351 strain has acquired enough mutations such that almost all of the neutralizing monoclonal antibodies tested were now ineffective against the variant. [bioRxiv(Preprint) 2021;doi:10.1101/2021.01.18.427166]

 Get covered, fast!

“Increased viral transmission creates greater opportunities for the emergence of SARS-CoV-2 variants,” wrote a panel of experts led by Professor Arnaud Fontanet of Pasteur Institute in Paris, France, in a commentary column. [Lancet 2021;doi:10.1016/S0140-6736(21)00370-6]

As the virus replicates, each cycle presents an opportunity for mutations to develop — thus increasing the likelihood that an “escape mutation” rendering resistance to vaccination and antiviral treatments might arise.

The reduction in vaccine efficacy seen with the emergence of the South Africa B.1.351 variant brings “all the more reason why we should be vaccinating as many people as we possibly can … [because otherwise,] viruses have a playing field to mutate,” said the US White House health advisor Dr Anthony Fauci during a press briefing.

The speed at which the virus is evolving, with consistently high case counts in certain regions, highlights just how important it is to keep mitigation measures such as mask-wearing and social distancing in place, even with the availability of COVID-19 vaccines — until, at least, a high enough vaccine coverage has been achieved in the population.     

Meanwhile, success story in Israel is now hailed as a poster child for COVID-19 vaccination programme. Israel, being the fastest to vaccinate its population in the world — now with almost half of its population covered — is beginning to see new infections in the country plummeting.   

“The end of the pandemic is only possible when vaccines that are effective against circulating variants are distributed equitably across the world,” stated Fontanet and colleagues.

“As high-income countries race to immunize their populations within months, they leave themselves vulnerable to SARS-CoV-2 evolving in other countries to a new lineage that vaccines might not protect well against,” they warned.

 

 

*NERVTAG: New and Emerging Respiratory Virus Threats Advisory Group
**NIH: National Institutes of Health