WHO Overview & Risk Assessment On SARS-CoV-2 Variants

#15,674

Overnight the World Health Organization published a lengthy, and detailed, overview of (4) SARS-COV-2 variant, including the original European D614G mutation last winter, the Mink variants reported this past fall, and two new variants (UK and South African) reported in December of 2020. 

These aren't the only variants to appear by a long shot, but they are among the most worrisome.  Most variants are evolutionary failures and are unable to compete with existing strains, or they convey no advantage to the virus. 

But these four have demonstrated biological `fitness', and they appear to increased the transmissibility of the virus or to have reduced virus neutralization in humans, either of which could exacerbate the pandemic. 

While there are no blockbusters in this reports (i.e. Further investigations are required to understand the impact of specific mutations on viral properties and the effectiveness of diagnostics, therapeutics and vaccines.) this report provides an excellent overview of the problem, and the steps the WHO and public health agencies are taking to address it. 

SARS-CoV-2 Variants

Disease Outbreak News
31 December 2020

SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a large number of people; causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and vulnerable populations; interrupting routine healthcare services; disruptions to travel, trade, education and many other societal functions; and more broadly having a negative impact on peoples physical and mental health. 

Since the start of the COVID-19 pandemic, WHO has received several reports of unusual public health events possibly due to variants of SARS-CoV-2. WHO routinely assesses if variants of SARS-CoV-2 result in changes in transmissibility, clinical presentation and severity, or if they impact on countermeasures, including diagnostics, therapeutics and vaccines. Previous reports of the D614G mutation and the recent reports of virus variants from the Kingdom of Denmark, the United Kingdom of Great Britain and Northern Ireland, and the Republic of South Africa have raised interest and concern in the impact of viral changes.

A variant of SARS-CoV-2 with a D614G substitution in the gene encoding the spike protein emerged in late January or early February 2020. Over a period of several months, the D614G mutation replaced the initial SARS-CoV-2 strain identified in China and by June 2020 became the dominant form of the virus circulating globally. Studies in human respiratory cells and in animal models demonstrated that compared to the initial virus strain, the strain with the D614G substitution has increased infectivity and transmission. The SARS-CoV-2 virus with the D614G substitution does not cause more severe illness or alter the effectiveness of existing laboratory diagnostics, therapeutics, vaccines, or public health preventive measures.

In August and September 2020, a SARS-CoV-2 variant linked to infection among farmed mink and subsequently transmitted to humans, was identified in North Jutland, Denmark. The variant, referred to as the “Cluster 5” variant by Danish authorities, has a combination of mutations not previously observed. Due preliminary studies conducted in Denmark, there is concern that this variant has may result in reduced virus neutralization in humans, which could potentially decrease the extend and duration of immune protection following natural infection or vaccination. Studies are ongoing to assess virus neutralization among humans with this variant. To date, following extensive investigation and surveillance, Danish authorities have identified only 12 human cases of the Cluster 5 variant in September 2020, and it does not appear to have spread widely.

On 14 December 2020, authorities of the United Kingdom reported to WHO a variant referred to by the United Kingdom as SARS-CoV-2 VOC 202012/01 (Variant of Concern, year 2020, month 12, variant 01). This variant contains 23 nucleotide substitutions and is not phylogenetically related to the SARS-CoV-2 virus circulating in the United Kingdom at the time the variant was detected. How and where SARS-CoV-2 VOC 202012/01 originated is unclear. SARS-CoV-2 VOC 202012/01 initially appeared in South East England but within a few weeks began to replace other virus lineages in this geographic area and London. As of 26 December 2020, SARS-CoV-2 VOC 202012/01 has been identified from routine sampling and genomic testing conducted across the United Kingdom . Preliminary epidemiologic, modelling, phylogenetic and clinical findings suggest that SARS-CoV-2 VOC 202012/01 has increased transmissibility. However, preliminary analyses also indicate that there is no change in disease severity (as measured by length of hospitalization and 28-day case fatality), or occurrence of reinfection between variant cases compared to other SARS-CoV-2 viruses circulating in the United Kingdom.1 Another of the mutations in the VOC 202012/01 variant, the deletion at position 69/70del was found to affect the performance of some diagnostic PCR assays with an S gene target. Most PCR assays in use worldwide will use multiple targets and therefore the impact of the variant on diagnostics is not anticipated to be significant. Laboratory evaluation has demonstrated no significant impact on the performance of antigen-based lateral flow devices. As of 30 December, VOC-202012/01 variant has been reported in 31 other countries/territories/areas in five of the six WHO regions.

On 18 December, national authorities in South Africa announced the detection of a new variant of SARS-CoV-2 that is rapidly spreading in three provinces of South Africa. South Africa has named this variant 501Y.V2, because of a N501Y mutation. While SARS-CoV-2 VOC 202012/01 from the UK also has the N501Y mutation, phylogenetic analysis has shown that 501Y.V2 from South Africa are different virus variants. In the week beginning 16 November, routine sequencing by South African health authorities found that this new SARS-CoV-2 variant has largely replaced other SARS-CoV-2 viruses circulating in the Eastern Cape, Western Cape, and KwaZulu-Natal provinces. While genomic data highlighted that the 501.V2 variant rapidly displaced other lineages circulating in South Africa, and preliminary studies suggest the variant is associated with a higher viral load, which may suggest potential for increased transmissibility, this, as well as other factors that influence transmissibility, are subject of further investigation. Moreover, at this stage, there is no clear evidence of the new variant being associated with more severe disease or worse outcomes. Further investigations are needed to understand the impact on transmission, clinical severity of infection, laboratory diagnostics, therapeutics, vaccines, or public health preventive measures. As of 30 December, the 501Y.V2 variant from South Africa has been reported from four other countries to date.

Public health response

The authorities in the affected countries are conducting epidemiological and virological investigations to further assess the transmissibility, severity, risk of reinfection and antibody response to new variants. As one of the mutations (N501Y) – found in both the SARS-CoV-2 VOC 202012/01 and 501Y.V2 variants – is in the receptor binding domain, the authorities are investigating the neutralization activity of sera from recovered and vaccinated patients against these variants to determine if there is any impact on vaccine performance. These studies are ongoing.

Genomic data of the SARS-CoV-2 VOC 202012/01 and 501Y.V2 variants has been shared by the national authorities and uploaded to the Global Initiative on Sharing Avian Influenza Data (GISAID) and genomic surveillance of the virus continues, globally.

The following activities have been initiated:

• National authorities that have reported virus variants are undertaking intensified sampling to understand how widely these new variants are circulating.
• National scientific teams are studying the effect of the mutations on reinfection potential, vaccination, diagnostic testing, infection-severity and transmissibility.
• Researchers and government authorities are working with WHO and collaborating with members of the WHO SARS-CoV-2 virus evolution working group to assess epidemiologic, modelling, phylogenetic and laboratory findings as results become available.
• WHO is working with countries to identify how current surveillance systems can be strengthened or adapted to evaluate potential virus variations through ongoing systematic clinical and epidemiologic surveillance, establishment of genetic sequencing capacity where possible, and providing access to international sequencing services to send samples for sequencing and phylogenetic analysis.
• Risk communication and community engagement activities scaled up to explain the public health implications of SARS-CoV-2 variants to the public and emphasize the importance of maintaining ongoing preventive measures to reduce transmission such as wearing face coverings, practicing hand hygiene and cough etiquette, keeping physical distance, ensuring good ventilation and avoiding crowded places.

As part of WHO’s SARS-CoV-2 global laboratory network, which has monitored virus mutations from the start of the pandemic, a specific working group on virus evolution was established in June 2020, composed of experts in sequencing, bioinformatics, and in vivo and in vitro laboratory studies. The Virus Evolution Working Group works to 1) strengthen mechanisms to identify and prioritize (potentially) relevant mutations; 2) identify relevant mutations early and study the potential impacts related to viral characteristics (e.g. virulence, transmission) and effectiveness of available and future countermeasures (e.g. diagnostics, vaccines and therapeutics); 3) evaluate possible mitigation strategies to reduce the negative impact of mutations; and 4) study the impact of specific mutations, including laboratory-controlled in vitro and in vivo studies of variants. Sharing of full genome sequences is facilitating detailed analyses by partners. The Working Group is collaborating with international scientists with a broad scope of expertise in virology in general and coronaviruses specifically to better understand the research findings and support further studies.

WHO risk assessment

All viruses, including SARS-CoV-2, change over time, most without a direct benefit to the virus in terms of increasing its infectiousness or transmissibility, and sometimes limiting propagation (see Q&A on COVID-19 and related health topics ). The potential for virus mutation increases with the frequency of human and animal infections. Therefore, reducing transmission of SARS-CoV-2 by using established disease control methods as well as avoiding introductions to animal populations, are critical aspects to the global strategy to reduce the occurrence of mutations that have negative public health implications.

Preliminary data suggest that the growth rate and effective reproductive number is elevated in areas of the United Kingdom with community circulation of the novel variant VOC-202012/01. In South Africa, genomic data highlighted that the 501Y.V2 variant rapidly displaced other lineages circulating, and preliminary studies suggest the variant is associated with a higher viral load, which may suggest potential for increased transmissibility; however, this, as well as other factors that influence transmissibility, are subject of further investigation. Epidemiologic investigations are underway to understand the increase in cases in these communities and the potential role of increased transmissibility of these variants as well as the robustness of implementation of control measures. While initial assessment suggests that 202012/01 and 501Y.V2 do not cause changes in clinical presentation or severity, if they result in a higher case incidence, this would lead to an increase in COVID-19 hospitalizations and deaths. More intensive public health measures may be required to control transmission of these variants.

Further investigations are required to understand the impact of specific mutations on viral properties and the effectiveness of diagnostics, therapeutics and vaccines. These investigations are complex and require time and collaboration among different research groups. These studies are ongoing.

WHO advice

National and local authorities should continue to strengthen existing disease control activities, including monitoring their epidemics closely through ongoing epidemiological surveillance and strategic testing; conducting outbreak investigation and contact tracing; and where appropriate, adjusting public health and social measures to reduce transmission of SARS-CoV-2.

WHO further advises countries, where feasible, to increase routine systematic sequencing of SARS-CoV-2 viruses to better understand SARS-CoV-2 transmission and to monitor for the emergence of variants. Sequence data should be shared internationally through publicly accessible databases. In countries with sequencing capacity, WHO advises sequencing of isolates from a systematically selected subset of SARS-CoV-2 infections – the amount will depend on local capacities. Genetic sequencing should also be considered as part of investigations of unusual transmission events (e.g. increased transmission in spite of existing control measures) or unexpected disease presentation/severity. Where limited sequencing capacity exists, countries are encouraged to increase capacity in collaboration with public, academic and private sequencing laboratories, and may arrange sequencing at collaborating laboratories in the COVID-19 reference laboratory network.

While mutations of SARS-CoV-2 are expected, it is important to continue to monitor the public health implications of new virus variants. Any increased in transmissibility associated with SARS-CoV-2 variants could make control more difficult. Current disease control measures recommended by WHO continue to be effective and should be adapted in response to increasing disease incidence, whether associated with a new variant or not.

Prevention advice and communications for the public should be further strengthened, including precautions to protect yourself and others such as physical distancing, wearing a mask, keeping rooms well ventilated, avoiding crowds, cleaning hands, and coughing into a bent elbow or tissue. Moreover, infection prevention and control guidance and measures should reinforced, including:

• Use appropriate personal protective equipment when caring for people suffering from an acute respiratory illness;
• Practice frequent hand-washing, especially after direct contact with ill people or their environment
• Practice cough etiquette (maintain distance, cover coughs and sneezes with disposable tissues or clothing, and wash hands)
• Enhance standard infection prevention and control practices in hospitals, especially in emergency departments
• Wear masks where appropriate, ensure good ventilation where possible and avoid crowded places

WHO has recently published an interim guidance – "Considerations for implementing a risk-based approach to international travel in the context of COVID-19", recommending the following principles for international travelers in the context of COVID-19 Pandemic:

• Confirmed, probable and suspected cases, and contacts of confirmed or probable cases should not travel
• Persons with any sign or symptom compatible with COVID-19 should not travel, unless COVID-19 diagnostic testing has been conducted and SARS-CoV-2 infection has been ruled out as the cause for illness
• Persons who are unwell should be advised to postpone travel
• Persons at risk of developing severe disease from COVID-19, including people 60 years of age or older or those with comorbidities that present increased risk of severe COVID-19 (e.g. heart disease, cancer and diabetes) should be advised to postpone travel
• Depending on local restrictions, persons residing in areas where community-wide movement restrictions are in place should not be allowed to travel for non-essential purposes
• In case of symptoms suggestive of acute respiratory illness either during or after travel, travelers are encouraged to seek medical attention and share their travel history with their health care provider

Health authorities should work with travel, transport and tourism sectors to provide travelers, including to and from the countries affected by the new variants, with aforementioned information, via travel health clinics, travel agencies, conveyance operators and at points of entry, as well as communities adjacent to land borders with affected countries.

The interim guidance also provides countries with a risk-based approach to decision-making, calibrating travel-related risk mitigation measures in the context of international travel, aiming at reducing travel-associated exportation, importation and onward transmission of SARS-CoV-2 while avoiding unnecessary interference with international traffic. Some countries have recently introduced travel restrictions as a precautionary measure in response to the appearance of new variants. WHO recommends that all countries take a risk-based approach for adjusting measures in the context of international travel, which includes assessing local transmission, health services capacity, what is known about the level of transmissibility of specific variants; social and economic impact of restrictions; and adherence to public health and social measures. National authorities are encouraged to publish their risk assessment methodology and the list of departure countries or areas to which restrictions apply; and these should be updated regularly.

In line with the advice provided by the Emergency Committee on COVID-19 at its most recent meeting, WHO recommends that States Parties should regularly re-consider measures applied to international travel in compliance with Article 43 of the International Health Regulations (2005) and continue to provide information and rationale to WHO on measures that significantly interfere with international traffic. Countries should also ensure that measures affecting international traffic are risk-based, evidence-based, coherent, proportionate and time limited.

In all circumstances, essential travel (e.g., emergency responders; providers of public health technical support; critical personnel in transport and security sector such as seafarers; repatriations; and cargo transport for essential supplies such as food, medicines and fuel) identified by countries should always be prioritized and facilitated.

For more information on COVID-19, please see:
WHO COVID-19 information
WHO Technical interim guidance for COVID-19
WHO COVID-19 Weekly Epidemiological Update and Weekly Operational Update
WHO Considerations for implementing a risk-based approach to international travel in the context of COVID-19
WHO Dashboard for COVID-19
WHO Public Health and Social Measures
Global Initiative on Sharing Avian Influenza Data (GISAID)


1 Public Health England. Investigation of novel SARS-CoV-2 variant, Variant of Concern 202012/01 Technical briefing 2- 28