The Variants Ratchet Up the Pressure

The biggest questions at this moment in the pandemic concern emerging variants.

Over the past two weeks in preprint publications, we have learned:

• Viral antigen tests remain effective in their ability to detect cases of COVID-19 driven by new variants. New objective comparisons of viral antigen tests: Clinitest; RAY Crispr; Panbio.

• Good news: Israel is the first real-world example of what we can expect from a mass vaccination campaign. Beginning Dec. 20 with the Pfizer / BioNTech mRNA vaccine, 89% of Israelis 60 and over had either recovered or been vaccinated through Feb. 2: early returns show 41% fewer cases, and ~50% lower mortality in that age group.

• Single dosing of the Pfizer / BioNtech mRNA vaccine is a viable strategy in a supply-constrained world, even though the vaccine was developed to boost immunity in a two-dose formulation. For people who already have some natural immunity from a prior COVID-19 infection, a single vaccine dose could be advisable.

• Many scientists are evaluating what the emerging strains of SARS-CoV-2 mean for control of the pandemic.

Key remaining questions include:

• What strains are we most worried about and why?
• Can previously infected COVID recovered individuals be re-infected by these new variants?
• Do they threaten to derail our current testing strategies, treatment protocols, and vaccine effectiveness?
• What should we do about them?

What strains are we most worried about and why?

A word on biology: all viruses evolve new point mutations (aka variants) all the time, and the vast majority of these reduce strain fitness. Fitness means that a particular strain outcompetes all others to become the dominant source of infection in a region. A particular strain’s fitness may be based on spreading faster or more easily and/or because it is better at escaping the immune system. 

Both of these aspects are concerning, but as we get better at countermeasures (antibody treatments and vaccines), it is immune escape that most threatens to derail our hopes for beating the epidemic.  Fitness results from the net benefit of all the underlying positive, neutral and beneficial mutations that have evolved and are packaged with a “headline” mutation. 

We tend to focus on single point differences within a strain. Currently, the greatest concern stems from the E484K mutation, (found in COVID-19 samples from South Africa and Brazil). The next most concerning mutation is known as N501Y (first identified in the UK, but present in South African, Brazilian and US strains also). In distant 3^rd place, we there’s the Y453F mutation (the Danish mink strain). These new mutations have now all combined with the D614G mutation, which became the globally dominant form of SARS-CoV-2 in February 2020. 

It can be misleading to focus on single headline mutations only. For example, see a small study in the UK that found that the Pfizer/BioNTech vaccine, originally developed based on the genetic code of SARS-CoV-2 from Wuhan in January 2020, was equally effective in neutralizing a modified strain containing only the 3 key UK mutations (N501Y; A570D; del69/70).

That sounded good at first glance. But when faced with all 23 mutations present in the wild type UK B.1.1.7 variant, the Pfizer / BioNTech vaccine was 3.9x less neutralizing. Of course, we know that even a reduction of this magnitude is still highly effective in mitigating or protecting from the disease for most cases, but we do not know how much of an immune response is enough to protect individuals, or whole populations, from illness.

Carefully controlled lab tests of new viral variants against the vaccines are essential, but can be only directional guides to what might happen in the real clinical world. Unfortunately, the strains that embed the variants of most concern, are now spreading around the world and appear to be fueling recent growth waves of COVID-19, especially in the UK. 

We are in a scramble to figure out what they mean against a background of limited but growing scientific data. There is evidence that N501Y accelerates transmission by 50-70% (10x greater affinity to the ACE2 receptor on human cells reduces the viral load necessary for successful infection). Plus, early data on N501Y indicates that it also contributes to more serious disease and immune escape. E484K appears to drive immune escape more strongly than N501Y, making the combination present in the South African strain of great concern.

If we have a circulating variant that is more transmissible, causes more severe illness, and is more able to escape vaccine-induced immune responses – then we are truly up against a much more formidable virus.

Can recovered people be re-infected by the new variants?

Until the E484K variant was identified, the answer was no.Now that we see E484K containing strains in both South Africa and Brazil, the early answer appears to be yes. Before the emergence of the E484K variant, there was a consensus that for all but the immune-compromised, natural infection protected against reinfection for at least 6 months or longer. Reinfection cases had been documented, but at very low rates (e.g. 0.16% of previously COVID positive UK health workers). 

Most concerning is the emergence of a second — more lethal — wave of infection in Manaus, Brazil. The experience from Manaus implies novel spike variants can re-infect those who have recovered from the strains circulating in early 2020. Manaus is an isolated community of 2 million in the Amazon rain forest, where effective control had been achieved by May 2020. By mid-December, an estimated 76% of the population had been previously infected and was presumably COVID-immune.

But that turned out to be an illusion. In January, a more transmissible and virulent strain (P.1, a derivative of the B.1.1.28 Brazil strain) was identified, supported by a case investigation of a patient who had recovered in late March but became reinfected in December. Data are preliminary and limited, but highly suggestive that the new strain in Brazil can overcome immunity gained from previous SARS-CoV-2 infection.

Do they threaten to derail our current testing strategies, treatment protocols, and/or vaccine effectiveness?

Individual test effectiveness will have to be continuously monitored for evasion, but none of the known variants have yet had a significant impact on test accuracy since most (all of the rapid antigen tests) detect the abundant nucleocapsid protein and its mRNA. Almost none target the mutated spike regions, and very, very few focus on the spike region alone.

Variants do threaten the highly specific monoclonal antibody-based therapies. The antibodies most effective at neutralizing the virus are those directed at very specific epitopes within the receptor binding domain of the spike protein. This is a small region, and is where the variants of most concern reside. There is evidence that the SARS-CoV-2 virus is able to generate variants to escape focused antibody therapies, but since very few of these have been used clinically to date, emerging strains must have been able to develop current immune mitigation strategies (e.g. E484K) even under the much wider pressure of the immune response to natural infection. 

Current vaccines are all designed to focus on the most effective aspects of response to natural infection i.e. to the spike protein, and so there is a parallel threat that the virus will be able to evolve further escape variants as vaccination is rolled out, and puts greater pressure on the virus to adapt or die. 

Notably, Israel is providing early data that vaccines will retain substantial effectiveness – the dominant strain in Israel is becoming the UK B.1.1.7 strain, and vaccine effectiveness is already apparent, but at lower levels than in clinical trials. 

The faster we vaccinate, the less opportunity there is for escape adaptation to occur and spread.

What should we do about emerging mutations?

We need to proactively adapt our vaccine portfolio to the strain mutations that are rapidly emerging and becoming dominant, while remaining vigilant that testing targets do not mutate away from current probes and primers.

For now, it appears that current vaccines still have adequate, albeit reduced, efficacy in the face of emerging variants. However, time is not on our side – in the year it has taken for science to deploy vaccines against the original Wuhan sequence, the virus has evolved 4 novel mutations. Taken together, these mutations substantially enhance transmissibility and virulence. 

We have the ability to keep up, but only if we adopt a flu-vaccine-like timetable. In early 2020 Moderna, among others, developed their first vaccine candidate 4 days after publication of the SARS-CoV-2 genome on Jan. 12; two months later an improved candidate was beginning Phase I/II trials. The FDA granted an Emergency Use Authorization on Dec. 18.

This is light speed by the standards of prior novel vaccine approvals – a 10-year timeframe reduced to 10 months. Shortening traditional approval timelines, for new mRNA vaccine variations designed against the new variants, will be absolutely essential. A further reduction to 10 weeks or less is required to counter emerging mutations.

Safety is less concerning since vaccines will utilize unchanged packaging – this is akin to a slight modification like we see with flu vaccines each year. No major 30,000-volunteer study will be needed to demonstrate safety and efficacy. Variants require minimal changes to vaccine payloads, and testing targets. Efficacy can be monitored post-launch in a Phase IV manner since it will be reasonable to expect only improved efficacy from including novel point mutations in payload design.

The FDA sees the need for urgency. On Feb. 4, the FDA issued a statement on accelerated timetables for confronting the emerging variants – “We do not believe that there will be the need to start at square one with any of these products” (i.e. tests, therapies and vaccines). Few specifics were included, but keeping up with the variants means not only quickly adapting our vaccines, but also enhancing variant surveillance, evaluation and communication.  

We should not underestimate the degree of culture change required of both regulators and risk managers at vaccine companies if an adequately speedy response is to be successful. It’s a serious challenge. There’s no time to waste.