Variants may delay, not derail COVID-19 control

Analysis

SARS-CoV-2 has been changing at the genetic level from the start of the pandemic. The rate of change was comparable to other similar viruses.

More recently, variants have emerged which are more concerning, for several reasons:

• they present an unusually high accumulation of mutations compared to their direct ancestor;
• they share critical mutations which arose independently in different parts of the world;
• they arose in regions with high previous levels of the virus; or
• they coincided with a sudden surge in cases in a specific region even when containment measures were in place.

Currently, there are three variants of concern:

B.1.1.7

This was first identified in the United Kingdom from a surge of cases in the county of Kent even with containment measures in place, at a time when numbers were declining in the country (December 2020). Data confirms that the lineage is 50% more transmissible than the previously circulating lineage. Limited data also speculates that this variant might cause relatively severe disease. It has now been identified in 73 countries.

B.1.351

This was first observed in South Africa and is now identified in 31 countries. It is also thought to spread faster (see SOUTH AFRICA: Vaccine roll-out faces new complications - February 8, 2021).

P.1

This was first identified in Japan from travellers coming from Brazil. It is causing widespread cases in Manaus, an area previously hard-hit by COVID-19, raising questions whether this lineage escapes immunity acquired from previous infection. It has now been identified in nine countries (see BRAZIL: Amazonas faces mounting COVID crisis - January 15, 2021).

All three variants share a mutation called as N501Y which increases transmission by some 40% to 70%, but does not appear to reduce vaccine efficacy so far. However, B.1.351 and P.1 have additional mutations, including one called E484K which has the potential to evade immune responses.

Effectiveness reporting

Field trials of vaccines in South Africa have shown reduced efficacy (Pfizer, Janssen, Novavax, Moderna) against this variant. Preliminary clinical trial results of the Oxford/AstraZeneca vaccine showed 74% efficacy in the United Kingdom but only 22% in South Africa. The Novavax vaccine showed 89% efficacy in the United Kingdom but only 49% efficacy in South Africa, while the single-dose Johnson & Johnson showed 72% efficacy in the United States and 57% efficacy in South Africa -- though the vaccine also reported 85% protection against severe disease (see INT: New COVID-19 variants could prolong pandemic - January 29, 2021).

Reports of efficacy can be difficult to disentangle. Most vaccines report efficacy against symptomatic disease (mild, moderate or severe) as an end point which is quicker to identify. Asymptomatic infection is not easy to gather data for and requires regular extensive testing of all participants.

The differences in efficacy reported from inter-country trials represent mostly mild and moderate disease as numbers were not large enough to assess impact on severe disease (which occurs in an even smaller proportion of people). For all trials to date, efficacy against severe disease is expected to be higher than that for mild disease and this is still above earlier acceptable thresholds of around 50% and thus vaccines are likely to reduce hospitalisations and deaths. As such, complete failure of existing vaccines is unlikely but higher coverage will be needed with lower efficacy of vaccines.

Furthermore, relying on preliminary reports can be misleading. For example, the Oxford/AstraZeneca South Africa study was small (2,000 people) and recruited relatively healthy, young people and none of participants (in the placebo or vaccine teams) developed severe disease. Only 19 cases of mild or moderate disease developed among the vaccinated, versus 23 in the placebo group, resulting in an efficacy of 21.9% -- a very small number to draw conclusions from.

Lastly, most experimental data so far has come from antibody measurements and it is not yet known if these changes affect long-term T-cell immunity, though it is likely that T-cell responses will remain intact (see INTERNATIONAL: Immunity will shape pandemic's future - June 26, 2020).

Vaccine impact

Historically, except for influenza, not many diseases have required an update to vaccines based on strain type. For example, measles strains remain more closely related to each other over decades (new influenza strains can emerge annually).

Often this has been because vaccines can generate antibody responses across many parts of the virus (by using attenuated or killed virus). Sinopharm, Sinovac, Bharat Biotech and the proposed Valneva, which are not yet being produced widely, use this method.

In contrast, modern vaccines (virus-vectored, mRNA) target a specific region of a specific protein and a change in this region can affect how well antibodies perform. The Pfizer, Moderna, AstraZeneca, CanSino, Gamaleya and Janssen/Johnson and Johnson COVID-19 vaccines use this method. They are likely to need updated versions to take into account emerging variants, but are faster to produce (see INT: Multiple COVID-19 vaccines will aid distribution - November 5, 2020).

Normally vaccine trials that happen over years take into consideration circulating strains. A vaccine will usually be licensed if it caters to either all strains or the majority strain. The challenge with a new virus is that vaccine developers are acting retrospectively and do not have robust ways to predict how the virus may behave in the future (or what variants may emerge, although mutations are expected).

Outlook

In the medium term, while the virus keeps spreading, more lineages will probably emerge. However, vaccines could catch up by becoming broader spectrum. An ideal solution will be a vaccine that induces a broad neutralising capability or targets a part of the virus that may be less prone to mutations.

Alternatively, easily adaptable platforms could produce boosters/vaccine cocktails (which vector and mRNA vaccines offer, such as Pfizer, Moderna, Oxford/AstraZeneca and Gamaleya). This will, however, require a thorough knowledge of safety/efficacy considerations and the extent of trials and regulatory information required (which are the main cause of vaccination delay) to release boosters, especially if they are needed routinely. Some of this information will emerge as current vaccination progresses, and gaps are identified.

Another scenario could be that COVID-19 is reduced enough through social distancing interventions and existing vaccine coverage. This may negate the need for new types of vaccines against new variants. However, this will depend on how widespread vaccine coverage is globally, as well as duration of immunity to the disease (see PROSPECTS 2021: COVID-19 - November 19, 2020).