Variants

The following text will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give it early visibility.

By Bernd Sebastian Kamps
Copy-editor: Rob Camp

Published 31 January – Revised 20 Febuary

 

Weekly Summary | 20 February

B.1.1.7 in Europe

The more transmissible “English” variant B.1.1.7 will soon become the dominant strain in almost all countries of continental Europe. The current ‘flat pandemigram’ in most European countries might be deceiving – it could be the calm before the storm, most countries simply being in the middle of “two different epidemics: a small epidemic that is growing rapidly with the new variant, and a large epidemic of the original virus on the decline” (Adam Kucharski, cited by Dagorn 2021).

Figure 1. Flat ‘pandemigram’ in Europe in February 2021. The calm before the storm?

 

In some places, for example in the urban community of Dunkirk, France, vis-à-vis Kent, England, the cumulative 7-day incidence rate per 100,000 people reached 713 on 19 February. The share of the B.1.1.7 variant was estimated at 72% of cases and hospitals were seeing a large influx of patients (Stromboni 2021). Although ‘hard’ lockdowns are apt at controlling the new variants (see below: UK, Ireland, South Africa), the coming weeks may display very different scenarios in different countries (Figure 2).

Infection with B.1.1.7 is likely to be associated with an increased risk of hospitalization and death compared to infection with previously circulating viruses (NERVTAG 20210211).

Figure 2. March to May 2021: possible scenarios for national epidemics. Blue: new SARS-CoV-2 infections due to old variants; red: new SARS-CoV-2 infections due to new variants. On the left, mitigation measures succeed in keeping case numbers low until the general availability of vaccines for the adult population. On the left, an uncontrolled epidemic is fuelled by the higher transmissibility of the new SARS-CoV-2 variants. Graphic copyright: Süddeutsche Zeitung, 5 February (Berndt 2021).

 

B.1.1.7 and vaccines

The good news for B.1.1.7 is that current vaccines seem to retain efficacy against the variant. In Israel, the Pfizer-BioNTech vaccine has been shown to decrease the number of hospitalizations and deaths in vaccinated individuals (Amit 2021). In vivo data confirm that strains like B.1.1.7, B.1.1.298, or B.1.429, continue to be potently neutralized by sera from vaccine recipients (Garcia-Beltran 2021).

B.1.351

With regard to vaccine efficacy, the major concern is currently B.1.351 (first detected in South Africa) and, to a lesser extent, P.1 and P.2 (Brazil). The ChAdOx1-nCoV19 vaccine (AstraZeneca) did not show protection against mild-moderate COVID-19 due to B.1.351 (Madhi 2021). These findings were reproduced in an in vitro study which showed that B.1.351 variants escaped neutralizing vaccine responses like SARS-CoV-1 (!!; SARS 2002/2003) and bat-derived WIV1-CoV (Garcia-Beltran 2021). A relatively small number of mutations can therefore mediate potent escape from vaccine responses (Figure 3).

Figure  3. Fold decrease in neutralization for each pseudovirus relative to wild type for 22 vaccine recipients > 7 days after the second dose of the Pfizer-BioNTech vaccine. Source and copyright: Garcia-Beltran et al.

 

In the coming months, understanding innate (Schultze & Aschenbrenner 2021) and adaptive immune responses (Sette & Crotty 2021) will be helpful.

 


 

Introduction

With viruses, some mutations emerge while others recede. Rarely does one or more mutations confer a “selective advantage” to a new variant, for example enhanced transmissibility. When it does happen, such variants can then become the new dominant virus.

Over the last two months, several new SARS-CoV-2 variants have been described that are more transmissible, may escape both natural and vaccine-induced immunity and could impact COVID-19 morbidity and mortality. It is too early to assert that these variants will create a new pandemic within the pandemic, however, in countries like England, South Africa, Brazil, Ireland, Portugal and Israel, they may have modified the dynamic of the latest outbreaks for the worse. More transmissible SARS-CoV-2 variants will replace older variants – everywhere! Countries where the prevalence of these new variants is still low should anticipate rapid spread within the next weeks and months and plan ahead accordingly, ie closing/restricting borders, etc.

The current trio infernale:

Of note, although these variants evolved independently in different places around the globe, they share key mutations which are involved in receptor binding. This viral evolution is a normal process known from seasonal coronaviruses (Wong AHM 2017, Eguia 2020, Kistler 2021) and has recently been reproduced in vitro (Zahradnik 2020). Convergent evolution suggests that under the pressure of an increasing number of people having developed antibodies against SARS-CoV-2, the virus is developing a more perfect configuration.

The variant mutations may affect the COVID-19 pandemic in multiple ways:

  • Increased transmissibility
  • Increased severity of illness
  • Diminished protection from previous SARS-CoV-2 infection
  • Diminished response to vaccines
  • Diminished response to monoclonal antibodies

A higher rate of transmission will lead to more COVID-19 cases, increase the number of persons who need clinical care, exacerbate the burden on an already strained health care system, and finally result in more deaths (Galloway 2020). The increased transmissibility of new variants may therefore require an even more rigorous implementation of vaccination and mitigation measures (e.g., distancing, masking, and hand hygiene) to control the spread of SARS-CoV-2. These measures will be more effective if they are instituted sooner rather.



Epidemiology

Figure 4 shows the daily new confirmed COVID-19 cases in selected European countries. The increased transmissibility of B.1.1.7 has led to an increased number of infections in several countries, which in turn has led to higher hospitalization and death rates. Find more information about B.1.1.7 on page 29.

Figure 4. 19 February: Portugal, Spain, United Kingdom, France, Ireland, Italy, Germany. Daily new confirmed COVID-19 cases per million people (rolling 7-day average). Source: Our World in Data – Johns Hopkins University CSSE COVID-19 Data

 

Over the coming 4 to 6 weeks, the new variants, in particular B.1.1.7, will become dominant, with different outcomes in different countries (see above, Figure 2). For detailed epidemiological information on laboratory-confirmed cases in Europe, find the weekly ECDC COVID-19 surveillance report (https://covid19-surveillance-report.ecdc.europa.eu) and the weekly country overview (https://covid19-country-overviews.ecdc.europa.eu).

United Kingdom

In the UK, the first case of the B.1.1.7 variant (ie, 20B/501Y.V1 or VOC 202012/01) was retrospectively dated to 20 September. In Kent, a county in South East England, cases continued to increase during a lockdown in November, despite having the same restrictions as other regions. When, on 2 December, England lifted its lockdown, the proportion in England of B.1.1.7 continued to increase sharply in Kent and then rapidly in Greater London and other parts of the southeast (Kirby 2021), rising to over 70% at the beginning of January 2021. Areas with the highest B.1.1.7 incidence coincided with areas reporting higher levels of patient hospitalisation (Gravagnuolo 2021). In England, B.1.1.7 took around 6 weeks to go from less than 20% of cases to over 80% (Public Health England 20210126, Figure 5).

The good news from the UK: lockdowns are efficient against the SARS-CoV-2 variant too. After a peak of the rolling 7-day average on 9 January, the numbers started decreasing (Figure 6). Whether the spike protein mutation E484K which was detected in eleven B.1.1.7 sequences at the end of January 2021 (Public Health England 20210126) will eventually spread more widely, is unknown.

Figure 5. Weekly number (bars) and proportion (line) of B.1.1.7 (SGTF: “Sgene target failure”; deep purple) COVID-19 cases (7 September 2020 to 24 January 2021) (Public Health England 20210126).

 

Figure 6. United Kingdom, Ireland, Portugal, 19 February. Lockdowns are efficient against B.1.1.7. After a peak of the rolling 7-day average on 10 January (UK, Ireland) and 28 January (Portugal), the number of daily new confirmed SARS-CoV-2 cases decreased rapidly. Source: Our World in Data – Johns Hopkins University CSSE COVID-19 Data.

 

In the UK, the fatality rate in people aged 80 or older dropped more quickly than for younger age groups who had yet to be vaccinated (Leach 2021) (Figure 7).

Figure 7. UK, 14 February. Deaths in over-70s are now falling faster than in younger age groups, which is likely to be influenced by vaccination (Leach 2021). Source: The Guardian.

 

South Africa

In South Africa, B.1.351 (also called 501Y.V2) was first detected in early October 2020 and is now the most prevalent variant in the country. Like B.1.1.7, it has an increased transmissibility. After a peak of the rolling 7-day average on 11 January, the numbers in South Africa decreased rapidly (Figure 8).

As of 12 February, B.1.351 has been identified in more than three dozen countries. Cluster of this variant are currently being investigated in France and Austria (Tyrol). Israel and the UK have also reported cases or clusters of non-travel-related B.1.351 cases (ECDC 20210121). Lockdowns are efficient against B.1.351. Find more information about B.1.351 on page 32.

Figure 8. South Africa, 19 February. Lockdowns are efficient against B.1.351. After a peak of the rolling 7-day average on 11 January, the number of daily new confirmed SARS-CoV-2 cases decreased rapidly. Source: Our World in Data – Johns Hopkins University CSSE COVID-19 Data.

Brazil

In January 2021, the P.1 variant was identified in 42% (13 out of 31) of RT-PCR positive samples collected between 15 and 23 December in Manaus, Amazonia, Brazil (Faria 2021). At the time, Manaus was experiencing an upsurge in COVID-19 cases. P.1 has 10 mutations in the spike protein (Faria 2021) and some, including N501Y and E484K, have been reported in B.1.1.7 and B.1.351, the variants first detected in the UK and South Africa. Find more information about P.1 and on the situation in Manaus in January 2021 on page 34.

Switzerland

The proportion of B.1.1.7 among confirmed SARS-CoV-2 cases has recently been estimated to be 86% in the canton of Geneva, 47% in Bern, 59% in Zurich, and 61% in Switzerland overall (Figure 9) (Althaus 2021). The authors also estimate the increase in transmissibility to be around 40% to 50%.

Figure 9. 19 February. Increase in the proportion of SARS-CoV-2 variants among positive samples in Switzerland and Denmark. Note that the projected trajectories for Zurich and Switzerland are overlapping. Error bars and shaded areas correspond to 95% confidence intervals of the data (blue) and model (red), respectively. Source and copyright: Althaus 2021.

 

The proportion of B.1.1.7 among confirmed SARS-CoV-2 cases increases at a similar pace in different regions of Switzerland. Geneva appears to be around two weeks ahead of the rest of Switzerland (Figure 10).

Figure 10. The proportion of B.1.1.7 among confirmed SARS-CoV-2 case increases at a similar pace in different regions of Switzerland. Geneva appears to be around two weeks ahead of the rest of Switzerland. Source and copyright: Christian Althaus, https://twitter.com/C_Althaus/status/1360177933155983361.

Israel

Due to a swift start of vaccination targeted toward older ages, 90% of people over 60 had received the first dose of vaccine by 6 February. As a result, 75% of recent new infections have occurred in people younger than 30 years (Figure 11).

Figure 11. Israel, 6 February: Confirmed COVID-19 cases by age group – indexed to the start of the vaccination campaign. The values for each age group are indexed to the cases reported during the week of December 19, 2020, when vaccination against COVID-19 started in Israel. This means the number of cases in that week is given a value of 1. Source: Our World in Data – Link: https://ourworldindata.org/vaccination-israel-impact

 

Israel is an example of how challenging B.1.1.7 can be. Even with an extended vaccination program plus a national lockdown, the third COVID-19 wave is only slowly coming under control. The high prevalence of B.1.1.7 is probably causing the epidemic to drag on for much longer than would otherwise be the case and is partly responsible for a late decline in the number of new cases (Figure 12, red line) and deaths (black line) after the 27 December lockdown. Of note, with more than 2 million children who cannot yet receive the coronavirus vaccine, Israel will not reach herd immunity anytime soon.

Figure 12. SARS-CoV-2 cases in Israel. 13 February 2021. Impact of mass vaccination on the pandemic. The rolling 7-day average of new SARS-CoV-2 cases is shown in red circles (left vertical axis), the rolling 7-day average of deaths as a plain black line (right vertical axis). The percentage of people that have received at least one vaccine dose is shown in green squares. The percentage of people that have been fully vaccinated is shown in green-yellow crosses. As the country entered a third lockdown on 27 December, the evolution of daily new cases and deaths are influenced by the lockdown measures, transmissibility of circulating viruses and the vaccination campaign.

 

Four weeks after the peak in mid-January, there was a 55% reduction in cases, 40% reduction in hospitalizations, 35% reduction in critically ill patients, and a 35% reduction in mortality in people 60 years and older, who were prioritized to get the vaccine first. (Segal 2021).

Belgium

The following Wenseleers curves describe the “One month – 20 to 80” rule of the current B.1.1.7 epidemic (Figure 13). Within one month, the percentage of the B.1.1.7 variant progresses from 20% to 80% in a given population.

Figure 13. Relative abundance of B.1.1.7 in England and Belgium. Other European countries, for example France, Denmark, Germany, Italy, Spain, and the US are expected to follow the same steep pattern within weeks. Source and copyright: Tom Wenseleers, https://bit.ly/3pJP7Db.

Austria

In 2020, thousands of skiers infected in Ischgl (pronounced “ISH-gul”) and surrounding villages in Tyrol, Austria, carried SARS-CoV-2 to more than 40 countries on five continents (Spanish article: Sampedro 2020). Many of Iceland’s first cases and nearly half of the earliest cases in Norway could be traced to Austrian ski holidays. In February 2021, Tyrol detected more than 300 people with the B.1.351 variant. For the rest of the winter, Tyrol may not be a good place to go skiing.

Denmark

In mid-February, with Denmark still in lockdown and cases declining rapidly, B.1.1.7 was continuing to increase in frequency. On 16 February, the Danish Statens Serum Institut published the percentage of B.1.1.7 samples of the previous 6 weeks: 4%, 7%, 13%, 20%, 31% and 48% (DCGC 20210216) (Figure 14).

Figure 14. Number of B.1.1.7 cases per week (only the last 16 weeks shown) out of the total number of cases with a genome in parenthesis below. Copyright and source: Statens Serum Institute, DCGC 20210216.

 

The nationwide SARS-CoV-2 Rt reproduction number (‘Kontaktal’) for B.1.1.7 was 0,99 (SSI 20210209) (Figure 15) – infection levels were neither shrinking nor growing exponentially. The country has announced that they will soon test all positive COVID-19 test swabs for the presence of variants.

Figure 15. In Denmark, the nationwide SARS-CoV-2 Rt reproduction number (‘Kontaktal’) for B.1.1.7 has recently been 0.99 (SSI 20210209). Copyright and source: Statens Serum Institut, published 9 February 2021.

France

Dominance of B.1.1.7 is expected by the end of February-early March in France. In the absence of strengthened social distancing, a rapid growth of cases is expected in the next weeks (Di Domenico 2021) (Figure 16).

Figure 16. Projected weekly hospitalizations due to SARS-CoV-2 in France (top) and Ile-de-France (bottom), according to three scenarios: flexible re-containment like in November 2020 (left), current measures (center) or relaxation (pre-curfew). The green dotted lines represent the original virus, the green curve represents the variant B.1.1.7, the black curve is the result of both. Copyright and source: INSERM, published 14 February 2021.

 

In France, the proportion of B.1.1.7 increases by 50% every week. The new strain represents currently around 36% of newly detected SARS-CoV-2 cases (Le Monde, 19 February).

B.1.351 and P.1 (first detected in South Africa and Brazil, respectively) now represent 4% to 5% of new cases. Over the last week, some 500 cases of B.1.351 and P.1 have been detected in local outbreaks in Moselle (Le Monde, 12 February). Various mayors of the region are considering a lockdown. Find regularly updated information about B.1.351 strains in France at https://nextstrain.org/groups/neherlab/ncov/S.E484?f_country=France (Figure 17).

Figure 17. France: phylogenetic analysis of SARS-CoV-2 clusters in their international context – cluster S.E484 (B.1.351). Copyright and source: Nextstrain, Maintained by Emma Hodcroft and Richard Neher. https://nextstrain.org/groups/neherlab/ncov/S.E484?f_country=France

Germany

Data transmitted to COVID Reference by a reliable healthcare source showed that in certain German regions, “30.5% of samples analyzed from 13 to 19 February were B.1.1.7 positive and 0.6% B.1.351 positive” (Anonymous, personal communication, 20 February). Remember our summary, page 3: The prevalence of B.1.1.7 progresses from 20% to 80% in 4 weeks (in the case of Germany, mid-March).

US

New York was likely one of the key hubs for introduction and domestic spread of B.1.1.7. (Alpert 2021). The data highlight the relative ease with which SARS-CoV-2 variants can spread undetected throughout the US.

A recent paper reported the analysis of 212 B.1.1.7 genomes collected in the US from December 2020 to January 2021. The authors found a doubling rate of a little over a week and an increased transmission rate of 35-45% (Washington 2021) and predict that the US is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant. Updated data are available at Helix 202102 (Figure 18).

Health authorities should wait a few weeks before eliminating effective mitigation measures such as mask mandates and bans on gatherings. A weekly updated COVID tracker is available at the CDC website (CDC Tracker 2021).

Figure 18. Trends in B.1.1.7 infections in the US. Source: Helix.

 

Transmission

The epidemiological consequences of B.1.1.7, B.1.351, P.1 and those variants to come are currently not predictable. It is acknowledged that they probably all have a substantial transmission advantage (+ 25%?, + 50%?, + 70%?) (Davies 2020, Volz 2021, Leung 2021, Public Health England 20210126). Increased transmission will lead to more SARS-CoV-2 infections and more hospitalizations and might significantly increase the number of deaths over the coming months. Figure 19 depicts a simplified scenario showing the number of new deaths every six days from three different viral strains, assuming each strain started from 10.000 infections. It shows how a more infectious virus may lead to more deaths.

There is now evidence that vaccines might have an impact on the transmissibility of SARS-CoV-2. Two studies show a decrease of viral load by 1.6x to 20x in individuals who were positive for SARS-CoV-2 (Petter 2021, Levine-Tiefenbrun 2021). It may take some time to quantify the impact on local epidemics. (Mallapaty 2021).

Figure 19. A more infectious virus could lead to many more deaths. Simplified, hypothetical scenario showing the number of new deaths every six days from three different virus strains, assuming each strain started from 10.000 infections. Source: Adam Kucharski, Associate Professor, London School of Hygiene and Tropical Medicine.

 

Clinical Consequences

It is now likely that infection with B.1.1.7 is associated with an increased risk of hospitalization and death compared to infection with previsously circulating viruses (NERVTAG 20210211). One study, analyzing a large database of SARS-CoV-2 community test results and COVID-19 deaths,  found that among B.1.1.7 cases, the hazard of death may be more than 50% higher. For a male aged 55–69, the absolute risk of death would increase from 0,6% to 0,9% over the 28 days following a positive test in the community (Davies 2021).

There are as yet no data on different clinical outcomes after infection with B.1.351 or P.1.

Immune escape

The Question of the Year 2021 is, “Will immunity – natural or vaccine-induced – be effective against evolving SARS-CoV-2 variants or will the variants be able to escape human immunity?” In other words: will B.1.1.7, B.1.351, P.1 or other upcoming variants be able to

  • Escape naturally acquired immunity
  • Escape vaccine induced immunity
  • Escape the effect of monoclonal antibodies

Acquired immunity

There is growing evidence for a long-lived and robust T cell immunity generated after natural SARS-CoV-2 infection (Neidleman 2020). Reinfections with phylogenetically distinct SARS-CoV-2 strains that have been reported were usually milder than the first episode (To 2020, Gupta 2020, Van Elslande 2020, Tillett 2021, Iwasak 2021), with only occasionally more severe disease being reported (Larson 2020). These reports are certainly only the tip of an iceberg of hundreds or thousands of potentially undetected reinfections worldwide; however, today, 9 months after the first COVID-19 wave, there is no documented epidemic of reinfections, not even in countries where B.1.1.7 has largely replaced the previously circulating SARS-CoV-2 strains. The prospect of reinfection with antigenically distinct variants is real but doesn’t seem thus far a major concern. In any case, interpreting antibody neutralization results should always take into account the role of T cell responses against the new variants. Skelly et al., while identifying a reduction in antibody neutralization which was most evident in B.1.351, found that the majority of the T cell response was directed against epitopes conserved across all three strains (Skelly 2021). The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in natural immune responses.

In this reassuring context, the case of Manaus, Brazil, may need to be interpreted. The city of 2 million in the Amazon region saw a first pandemic wave in spring 2020 and a second one starting at the end of the year. The second catastrophic wave came as a surprise (see the insert on page 37) because in September 2020, a pre-print paper reporting serological data of blood donors from Manaus had announced “COVID-19 herd immunity in the Brazilian Amazon” – as much as 66% of the population of Manaus had already have been infected with SARS-CoV-2 (Buss 2020). Three months later, the paper appeared in Science with the title “Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic” (Buss 2020b). Today, the question is why can there be such a catastrophic situation in Manaus at the end of January, with 400 people not finding a place in hospital and 73 people not finding an urgently needed place in intensive care units (Leandro Resende, CNN Brasil, 29 January) if “three-quarters” of the population had been immunized during the first first wave? Should we assume that immunity against SARS-CoV-2 wanes after less than a year? Or, worse, that new variants like P.1 are able to evade immunity? Or might it be suspect that there never was a 75% attack rate in Manaus? 40 years ago we would not have used data from blood donors to make predictions on the AIDS pandemic. Extrapolating data from blood donors to the general population may be risky even today. We should wait for more data and hope that the Lancet paper published on 27 January (Sabino, Buss 2021) was not a semi-retraction of a Science paper (Buss 2020b).

It is as yet unknown whether re-infection with newly emerging variants such as B.1.1.7, B.1.351 or P.1 is a widespread phenomenon or is limited to a few sporadic cases (Naveca 2021). In the coming months, it will also be crucial to understand the extent to which such reinfection might contribute to the transmission of SARS-CoV-2 in previously exposed populations.

Recently, two brilliant reviews have discussed innate (Schultze & Aschenbrenner 2021) and adaptive immune responses (Sette & Crotty 2021).

Vaccine-induced immunity

Vaccine trials

The three vaccines licensed in Europe and the US – Pfizer-BioNTech’s Comirnaty as well as the Moderna and the Oxford-AstraZeneca vaccines – all target the spike protein of the virus, where B.1.1.7, B.1.351 and P.1 have several mutations. Will vaccine-induced neutralizing antibodies be effective against these variants? They probably will, albeit to a lesser extent (see Table 1).

ChAdOx1-nCoV19 (AstraZeneca) results are mixed. An unpublished non-peer-reviewed study reported that among participants in Phase II/III ChAdOx1 studies who had been infected with B.1.1.7, vaccine efficacy against symptomatic SARS-CoV-2 infection was comparable for B.1.1.7 and non-B.1.1.7 lineages (74,6% and 84%, respectively). Importantly, viral neutralization activity by vaccine-induced antibodies was 9-fold lower against B.1.1.7 than against a canonical non-B.1.1.7 lineage (Emary 2021). On the contrary, a ChAdOx1-nCoV19 trial in South Africa was disappointing – the AstraZeneca vaccine did not show protection against mild-moderate COVID-19 due to B.1.351 (Madhi 2021).

 

Table 1. Vaccine efficacy against new variants. Adapted from Eric Topol, https://bit.ly/3d3ZmPj, 7 February.
Vaccine manufacturer Participants Main efficacy findings
Efficacy against B.1.1.7    
Novavax 15.203 86% efficacy (vs 96% for previous variant)
AstraZeneca 4236 75% efficacy (vs 85% for previous variant)
Efficacy against B.1.351    
Janssen
(Johnson & Johnson)
~10.900 57% efficacy (72% in US)

No hospitalizations or deaths in South Africa

Novavax 4422 60% efficacy HIV negative (89% UK)

49% efficacy HIV positive

No hospitalizations or deaths in South Africa

AstraZeneca ~2000 “minimal protection vs mild-moderate infection”

 

Results from two clinical vaccine trials – Janssen’s ENSEMBLE and Novavax’s NVX-CoV2373 – have shown that the level of protection against moderate to severe COVID-19 infection was lower also in South Africa where B.1.351 has been the predominant variant of late. The Janssen vaccine candidate provided a level of protection against moderate to severe COVID-19 infection of 57% in South Africa and 72% in the United States (JNJ 20210129) while the Novavax product provided a level of protection against mild & moderate-to-severe COVID-19 infection of 60% in South Africa and 89,3% in the UK (Novavax 20210128). The Novavax trial also found that their vaccine candidate was more efficient against the original COVID-19 strain (95,6%) than against B.1.1.7 (85,6%).

It is quite possible that SARS-CoV-2 vaccines will need to be reformulated – a challenge most companies have already accepted (see Outlook, page 41). Find more information about immune escape on page 31 (B.1.1.7) and page 33 (B.1.351).

Real-world data (Israel)

SARS-CoV-2 vaccines work under real-world conditions. An unpublished non-peer reviewed study suggests that the Pfizer-BioNTech vaccine is between 66%-85% effective at preventing infection and 87%-96% effective for preventing severe disease (Aran 2021). How these raw figures translate into day-to-day graphics, is shown by Eran Segal, Hagai Rossman and colleagues who documented a 41% drop in COVID-19 infections in people aged 60 or older from mid-January to early February. During the same period, there was also a 31% drop in hospitalizations (Rossmann 2021, Figure 20). In people aged 59 and younger who received the vaccine later, cases dropped by only 12% and hospitalizations by 5%. The share of people aged 60 or older among those hospitalized for COVID-19 has been constantly falling since 15 January (Figure 21).

Figure 20. Comparison between the population aged 0-59 years old (orange line in A-D) and the population aged > 60 years old (blue line in A-D) during the vaccination period, on a nationwide level. Note: Figures A-D are presented with 2 different y-axis scales. A. Rolling weekly sum of new positive cases. B. Rolling weekly sum of new moderate or severe hospitalizations. C. Rolling weekly sum of new mild, moderate or severe hospitalizations. D. Rolling weekly sum of new severe hospitalizations. Source and copyright: Eran Segal, Hagai Rossmann, et al. – Link: http://bit.ly/36KhjOU

 

Figure 21. Israel – New hospitalizations for COVID-19 by age. Shown is the rolling weekly sum of COVID-19 hospitalizations. Data is available at the national level, plus breakdown by regions where vaccination began early or late. Source: Our World in Data. Link: https://ourworldindata.org/vaccination-israel-impact

 

Laboratory data

These real-life data were somewhat anticipated by in vitro studies. An analysis of 579 COVID patients samples collected between March and July 2020 suggested that the B.1.1.7 mutation would not result in immune evasion for a large majority of these COVID patients (Haynes 2021). An analysis of immune sera from individuals vaccinated with the Pfizer-BioNTech vaccine (Comirnaty™) showed that B.1.1.7 seems unlikely to escape vaccine-mediated protection (Muik 2021). The authors had investigated SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 16 participants in a previously reported trial with the mRNA-based COVID-19 vaccine Comirnaty. The immune sera had equivalent neutralizing titers to both variants.

In vitro data for B.1.351 and P.1 had already suggested greater concern. Both variants harbor the E484K (“Erik”) mutation (Tegally 2020, Voloch 2020) which seems to be the “bad boy on the block”. A recently published map of all amino acid mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) shows that the site where mutations tend to have the largest effect on antibody-binding and neutralization is E484 (Greaney 2021b). In a study by David H. Ho and colleagues, the serum of 12 people vaccinated with Moderna’s vaccine and 10 people vaccinated with the Pfizer-BioNTech vaccine was six to nine times less potent against B.1.351. Serum from 20 previously infected people was 11 to 33 times less potent (Wang P 2021). E484K accounted for much of the effect.

Escape from monoclonal antibodies

Monoclonal antibodies (mAb) – single or in combination – have received emergency use authorization (Chen P 2021, Baum 2020, Hansen 2020) and are promising candidates for prophylactic and therapeutic treatment for SARS-CoV-2. In November 2020, the FDA issued emergency use authorizations (EUA) for the combination casirivimab plus imdevimab (REGN-CoV2; Regeneron – FDA) and for bamlanivimab (Lilly – FDA) for the treatment of mild-to-moderate COVID-19 and who are at high risk for progressing to severe COVID-19 (see also the paragraph Monoclonal Antibodies in the Treatment chapter, page xxx). Even more mAbs are in the pipeline (Ju B 2020, Pinto 2020, Shi R 2020, Zost 2020, Dong J 2021). However, there is a now growing concern that new SARS-CoV-2 variants, especially B.1.351 which was first detected in South Africa, could impair the efficacy of current mAb therapies or vaccines.

A reminder: Epitope mapping had previously shown that antibodies are divided between those directed against the receptor-binding domain (RBD) of the spike protein and those directed against the N-terminal domain (NTD) of spike, indicating that both of these regions at the top of the viral spike are immunogenic (Liu L 2020). RBD is the prime target of the neutralizing response during infection (Rogers 2020, Piccoli 2020, Barnes 2020, Robbiani 2020) and most antibodies target this region (Piccoli 2020, Tzou 2020). NTD is the next most frequent target of investigational neutralizing antibodies.

Many of the B.1.1.7, B.1.351 and P.1 mutations reside in the RBD (also known as the receptor-binding motif—RBM) or in the antigenic supersite in NTD (Cerutti 2021, McCallum 2021). Recent studies have shown that a single amino-acid mutation (E406W) could fully escape the recently approved REGN-COV2, which consists of two antibodies targeting distinct structural epitopes (Starr 2021). Earlier, there was evidence that one of the spike protein mutations, E484K, might affect neutralization by some polyclonal and monoclonal antibodies (Greaney 2021b, Weisblum 2020). B.1.351 in particular may confer neutralization escape from multiple classes of SARS-CoV-2 directed monoclonal antibodies (Wibmer 2021, Liu Y 2021, Wu K 2021, Wang Z 2021).

Recently, David Ho, Pengfei Wang and colleagues presented a detailed picture of mAb-affecting mutation. After creating VSV-based SARS-CoV-2 pseudoviruses that contained each of the individual mutations as well as one with all 8 mutations of B.1.1.7 (UK∆8) and another with all 9 mutations of B.1.351 (SA∆9), they measured their susceptibility to neutralization by 30 mAbs. The results (see the details in Table 2) are sobering (Wang P 2021):

Table 2. RBD-directed antibodies. Fold-change in IC50 of neutralizing mAbs against UK∆8 and SA∆9* relative to wild type virus.
UKΔ8 SAΔ9
RBD**-directed mAbs 2-36
(Liu L 2020)
COVA-1
(Brouwer 2020, Liu H 2020)
910-30
(Banach 2021)
-14.0 < -1000
2-15
(Liu L 2020)
< -1000
Bamlanivimab (LY-CoV555)
(Chen P 2021)
< -1000
C121
(Robbiani 2020)
< -1000
Casirivimab (REGN10933)
(Baum 2020, Hansen 2020, Weinreich 2020)
-58,8
2-7
(Liu L 2020)
Imdevimab (REGN10987)
(Baum 2020, Hansen 2020, Weinreich 2020)
C135
(Robbiani 2020)
S309
(Pinto 2020)
-3,1
NTD**-directed mAbs 5-24
(Liu L 2020)
< -1000 < -1000
4-8
(Liu L 2020)
< -1000 < -1000
4A
(Chi X 2020)
< -1000 < -406,6
2-27
(Liu L 2020)
-121,2

 

< -1000
4-19
(Liu L 2020)
-20,5 < -1000
* David Ho, Pengfai Wang and colleagues at Columbia University produced VSV-based SARS-CoV-2 pseudoviruses that contain each of the individual mutations as well as one with all 8 mutations of the B.1.1.7 variant (UK∆8) and another with all 9 mutations of the B.1.351 variant (SA∆9) and measured its susceptibility to neutralization by 30 mAbs (and also 20 convalescent plasma, and 22 vaccinee sera). For neutralization of UK∆8, only the activities of 910-30 and S309 are impaired, albeit modestly. For neutralization of SA∆9, however, the activities of 910-30, 2-15, LY-CoV555 (bamlanivimab), C121, and REGN10933 (casirivimab) are completely or markedly abolished. Other mAbs such as 2-36, COVA1-16 2-7, REGN10987 (imdevimab), C135, and S309 (which are directed to lower aspects of the “inner or outer side”; see details in the article) retained their activities against SAΔ9.

** RBD: Receptor-binding domain; NTD: N-terminal domain

 

  • B.1.1.7 (RBD) – For neutralization of UK∆8, only the activities of 910-30 and S309 were impaired, albeit modestly.  The decreased activity of 910-30 was mediated by N501Y, whereas the slightly impaired activity of S309 was unexplained.
  • B.1.351 (RBD) – For neutralization of SA∆9, however, the activities of 910-30, 2-15, LY-CoV555 (bamlanivimab), C121, and REGN10933 (casirivimab) are completely or markedly abolished. Other mAbs such as 2-36, COVA1-16 2-7, REGN10987 (imdevimab), C135, and S309 (which are directed to lower aspects of the “inner or outer side”; see details in the article) retained their activities against SAΔ9.

Against SAΔ9, the complete loss of activity of 2-15, LY-CoV555, and C121 is mediated by E484K; the complete loss for 910-30 is mediated by K417N; and the marked reduction for REGN10933 is mediated by K417N and E484K.

  • B.1.1.7 and B.1.351 (NTD) – Both UKΔ8 and SAΔ9 are profoundly resistant to neutralization by several antibodies.

The resistance of UKΔ8 to most NTD mAbs is largely conferred by 144del, whereas the resistance of SAΔ9 is largely conferred by 242-244del and/or R246I.

In other words, Lilly’s bamlanivimab (LY-CoV555), alone or in combination with CB6, was no longer able to neutralize SAΔ9. While REGN10933+REGN10987 and COV2-2196+COV2-2130 are seemingly unaffected, each of these combinations had a component that lost some neutralizing activity. Although S309 and the Brii-196+Brii-198 combination were not significantly impaired, their potencies were noticeably lower (Wang P 2021). In another study, B.1.351 and P.1 were partially (casirivimab, in REGN-COV2, Regeneron) or fully (bamlanivimab, Lilly) resistant to monoclonal antibodies and was less efficiently inhibited by serum/plasma from convalescent individuals or those vaccinated with the Pfizer-BioNTech vaccine (Hoffmann 2021). These findings suggest that antibody treatment of SARS-CoV-2 infection might need to be modified in areas where B.1.351 and related variants are prevalent. They also highlight the importance of combination antibody therapy in a context of expanding antigenic SARS-CoV-2 diversity.

Stiff winds ahead for manufacturers of monoclonal antibodies.

The Variants

Nomenclature

The pandemic spread of SARS-CoV-2 has resulted in the generation of tens of thousands of viral genome sequences. From the beginning there was a need for a rational and dynamic viral nomenclature that would account for the expanding phylogenetic diversity of SARS-CoV-2. Such a scheme has been proposed by Andrew Rambaut et al. and is now generally accepted (Rambaut 2020b). The new variants first discovered in the UK, South Africa and Brazil are called B1.1.1.7, B.1.351, and P.1, respectively (Table 3). Common mutations are shown in Table 4. A comparison of mutation in B.1.1.7 and B.1.351 is shown in Figure 22.

 

Table 3. The currently circulating variants of concern. Adapted from Eric Topol: https://bit.ly/2N1mSlh, 12 February
Official name B.1.1.7 B.1.351 P.1
Where first identified UK South Africa Brazil
Other names used in the scientific literature N501Y.V1
20B/501Y.V1
VOC 202012/1
N501Y.V2
20H/501Y.V2
VOC 202012/2
N501Y.V3
VOC 202012/3
Mutations 23 21 17
Spike mutations 8 9 10
Key RBD, spike mutations beyond N501Y in all 69/70 del, P681H, Y144 del, A570D E484K, K417N, orf1b deletion E484K, K417T, orf1b deletion
Other mutations, including N-terminal T716I, S982A, D1118H L18F, D80A, D215G, ∆242-244, R264I, A701V L18F, T20N, P26S, D138Y, R190S, H655Y
Transmissibility ∆ > 50% increased Not established Not established
Lethality ∆ Not resolved ? ?
Immune escape Partial

Novavax
(96% -> 86%)

AstraZeneca
(84% -> 75%)

Yes

Partial reduction in
3 vaccine trials

Likely

Not established

Countries reported 82 40 18

 

 

Table 4. Shared mutations in B.1.1.7, B.1.351 and P.1. Adapted from Andersen KG: https://bit.ly/2NUvnyy
B.1.1.7 B.1.351 P.1
69-70 del L18F L18F
Y144 del D80A T20N
D215G P26S
R246I D138Y
R190S
K417N K417T
E484K (still rare) E484K (Eric) E484K (Eric)
N501Y (Nelly) N501Y (Nelly) N501Y (Nelly)
A570D
D614G D614G D614G
P681H A701V H665Y
T716I T1027I
S982A
D1118H

 

Figure 22. Mutations in the viral spike identified in B.1.351 (SA) and B.1.1.7 (UK) in addition to D614G (Source and copyright: Wang P 2021 – Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization. bioRxiv 2021, posted 26 January. Full-text: https://doi.org/10.1101/2021.01.25.428137).

 

SARS-CoV-2 evolution

Viruses evolve (mutate)

  • when they come under pressure, or
  • when they are given weeks and months to do so.

Situations of pressure include areas where an explosive epidemic infects large proportions of the population, killing some, but making most people immune. In these settings or in settings where most people, but not all, are immunized through vaccination, only mutant variants that are able to spread despite existing post-infection immunity can sustain continuous chains of transmission.

In an entirely different situation, immunodeficient and chronically infected individuals can be silent incubators of accelerated viral evolution. Such infections are rare, and onward transmission from them presumably even rarer, but they are not improbable (Rambaut 2020). High rates of mutations have been reported in immunodeficient or immunosuppressed patients who were chronically infected with SARS-CoV-2. One paper describes the 154-day clinical course of a 45-year-old man with severe antiphospholipid syndrome who was receiving Immunosuppressants medication (Choi 2020). Of interest, amino acid changes were predominantly in the spike gene and the receptor-binding domain, which make up 13% and 2% of the viral genome, respectively, but harbored 57% and 38% of the observed changes. Another report describes the history of an immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia (Avanzato 2020). In this case, shedding of infectious SARS-CoV-2 was observed up to 70 days.

In the following, we will briefly discuss

  • B.1.1.7 (first detected in England)
  • B.1.351 (first detected in South Africa)
  • P.1 (first detected in Brazil)

B.1.1.7

History and epidemiology

On 14 December 2020, the UK reported to WHO the B.1.1.7 variant (referred to by the UK authorities as SARS-CoV-2 VOC 202012/01: Variant of Concern, year 2020, month 12, variant 01) (WHO 20201231). This variant was first detected in September 2020. Phylogenetic studies carried out by the UK COVID-19 Genomics Consortium soon showed that the new variant had an unusual accumulation of substitutions and was growing at a large rate relative to other circulating lineages (Volz 2021). Within weeks, B.1.1.7 began to replace other viral lineages and as early as November/December 2020, it became the dominant strain in England. As of 20 December 2020, the regions in England with the largest numbers of confirmed cases of the variant were London, the South East, and the East of England (Volz 2021). From there, B.1.1.7 quickly spread all over the country & around the world (Du Z 2021). Between 30 November 2020 and 20 December 2020, 41% of 9321 UK cases that had genomic sequencing data included were B.1.1.7 (Public Health England 20210105). As of 20 February, B.1.1.7 had been identified in 93 countries (Figure 23). A short graphical guide to B.1.1.7 has been published in the lay press by Corum & Zimmer.

Figure 23. Map of B.1.1.7 local transmission, 13 February 2021 | Colours indicate reports of imported cases (pink) or of local transmission (darker purple). Data is obtained from news reports and similar sources and is manually maintained. Source and copyright: PANGO lineages, Áine O’Toole and Verity Hill, Rambaut Group, University of Edinburgh.

 

Virology

B.1.1.7 has emerged with an unusually large number of mutations in the spike protein (deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H) as well as in other genomic regions (Rambaut 2020). At the moment of discovery, the accrual of 14 lineage-specific amino acid replacements was unprecedented. Three of these mutations are of particular concern:

  • Mutation N501Y is one of the six key amino acids interacting with ACE2 receptor and experimental data suggests that it increases ACE2 receptor affinity (Starr 2020). The tyrosine substitution has been shown to have increased binding affinity to the ACE2 receptor (Chan 2020). N501Y has been associated with increased infectivity and virulence in a mouse model (Gu H 2020). [Remember: the receptor binding domain (RBD) of the SARS-CoV-2 spike protein mediates viral attachment to ACE2 receptors. It is a major determinant of host range and a dominant target of neutralizing antibodies.]
  • Deletion 69-70 is one of a number of deletions observed in the N terminal domain of the spike protein (McCarthy 2020, Kemp 2020) and is associated with reduced sensitivity to neutralization by SARS-CoV-2 human convalescent serum. It also arose in the mink-associated outbreak in Denmark with the background of the Y453F RBD mutation, and in humans in association with the N439K RBD mutation, accounting for its relatively high frequency in the global genome data (~3000 sequences) (Rambaut 2020).
  • Mutation P681H is immediately adjacent to the furin cleavage site between S1 and S2 in spike. [The S1/S2 furin cleavage site of SARS-CoV-2 is not found in other human coronaviruses and has been shown to promote entry into respiratory epithelial cells and transmission in animal models (Hoffmann 2020).]

Transmission

Preliminary epidemiologic, modelling, phylogenetic and clinical findings suggest that B.1.1.7 is significantly more transmissible (+50% to +75%) than previously circulating variants (Leung 2020, Volz 2021). It has recently been suggested that B.1.1.7 might cause longer infections with similar peak viral concentration compared to non-B.1.1.7 variants. This extended duration would contribute to B.1.1.7 SARS CoV-2’s increased transmissibility (Table 5) (Kissler 2021).

 

Table 5. Longitudinal PCR tests performed in a cohort of 65 individuals infected with SARS-CoV-2 undergoing daily surveillance testing, including seven infected with B.1.1.7
B.1.1.7 non-B.1.1.7
Mean duration of the
proliferation phase
5.3 days

(2.7, 7.8)

(90% credible interval)

2.0 days

(0.7, 3.3)

Mean duration of the
clearance phase
8.0 days

(6.1, 9.9)

6.2 days

(5.1, 7.1)

Mean overall duration of infection
(proliferation + clearance phase)
13.3 days

(10.1, 16.5)

8.2 days

(6.5, 9.7)

Peak viral concentration 19.0 Ct

(15.8, 22.0)

20.2 Ct

(19.0, 21.4)

log10 RNA copies/ml 8.5

(7.6, 9.4)

8.2

(7.8, 8.5)

 

Clinical consequences

It is now likely that infection with B.1.1.7 is associated with an increased risk of hospitalization and death compared to infection with previsously circulating viruses (NERVTAG 20210211). Find more on page 18, Clinical Consequences.

Immune escape

The Novavax trial found that their vaccine candidate was more efficient against the original COVID-19 strain (95,6%) than against B.1.1.7 (85,6%) (Novavax 20210128). These data will now be confronted with in vitro studies which suggest that sera from individuals who have been infected with non-B.1.1.7 lineages show neutralising activity against B.1.1.7 virus, and vice versa (Public Health England 20210115). Another small study investigating 16 participants who had received the Pfizer-BioNTech vaccine showed that the immune sera had equivalent neutralizing titers to both the B.1.1.7 variant and the previous Wuhan reference strain. The authors concluded – maybe prematurely – that these data, together with the combined immunity involving humoral and cellular effectors induced by this vaccine, would make it unlikely that the B.1.1.7 lineage will escape Comirnaty-mediated protection (Muik 2021). In yet another in vitro study of human sera from 20 participants in the Pfizer-BioNTech vaccine trial, drawn 2 or 4 weeks after immunization with two 30 μg doses spaced 3 weeks apart, the neutralization GMT of the serum panel against a virus with three mutations from the variant first detected in South Africa (E484K + N501Y + D614G) was slightly lower than the neutralization GMTs against an N501Y virus or a virus with three mutations from the UK variant (Δ69/70 + N501Y + D614G) (Xie X 2021). Although B.1.1.7 is harder to neutralize, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination seems unlikely (Supasa 2021).

B.1.351

History and epidemiology

On 18 December, national authorities in South Africa announced the detection of a new SARS-CoV-2 variant. The earliest detection had been traced back to October 2020 (South African Government 20201218). It emerged in a severely affected metropolitan area, Nelson Mandela Bay, located on the coast of the Eastern Cape Province. B.1.351 rapidly spread and largely replaced other SARS-CoV-2 viruses circulating in the Eastern Cape, Western Cape, and KwaZulu-Natal provinces. Within weeks it became the dominant lineage in the Eastern Cape and Western Cape Provinces (Tegally 2020, WHO 20201231).

As of 20 February, B.1.351 had been identified in 45 countries (Figure 21). Several B.1.351 clusters have been found in several French regions. (Figure 24).

Figure 24. Map of B.1.351 local transmission, 13 February 2021 | Colours indicate reports of imported cases (pink) or of local transmission (darker purple). Data is obtained from news reports and similar sources and is manually maintained. Source and copyright: PANGO lineages, Áine O’Toole and Verity Hill, Rambaut Group, University of Edinburgh.

 

Virology

The first description of the B.1.351 lineage found 8 mutations within two immunodominant domains of the spike protein: one cluster in the N-terminal domain (NTD) that includes four substitutions and a deletion (L18F, D80A, D215G, Δ242-244, and R246I), and another cluster of substitutions including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) (Tegally 2020). Unlike the B.1.1.7 lineage detected in the UK, B.1.351 does not contain the deletion at 69/70.

Transmission

While the full significance of the B.1.351 mutations described above is not yet clear, the genomic and epidemiological data suggest that this lineage may be associated with increased transmissibility (Tegally 2020). A mathematical model has estimated that B.1.351 could be 50% more transmissible than previously circulating variants in South Africa (Pearson 2021).

Clinical consequences

At this stage, there is no clear evidence to suggest that B.1.351 has any impact on disease severity. A more precise picture will evolve over the next few months.

Immune escape

The AstraZeneca vaccine ChAdOx1-nCoV19 did not show protection against mild-moderate COVID-19 due to B.1.351 (Madhi 2021). 23/717 (3.2%) placebo and 19/750 (2.5%) vaccine recipients developed mild-moderate Covid-19. Of the primary endpoint cases, 39/42 (92.9%) were the B.1.351 variant – against which vaccine efficacy was 10.4%.

Preliminary data of a clinical trial on Novavax’s protein-based COVID-19 vaccine candidate NVX-CoV2373 suggest reduced vaccine efficacy against B.1.351. In the South Africa trial that enrolled over 4400 patients, efficacy was 60% (95% CI: 19,9 – 80,1) for the prevention of mild, moderate and severe COVID-19 disease. That was significantly lower than the 89,3% efficacy found in an analogous trial in the UK (Novavax 20210128). In South Africa, 29 cases were observed in the placebo group and 15 in the vaccine group. During the study period, B.1.351 was widely circulating in South Africa. Preliminary sequencing data for 27 of 44 COVID-19 events showed that 92,6% (25 out of 27 cases) were B.1.351 (Novavax 20210128). Equally preliminary data of Janssen’s clinical ENSEMBLE trial inform that efficacy of Ad26.COV2.S (Mercado 2020) was 57% in South Africa (which has B.1.351), 66% in Latin America and 72% in the United States (JNJ 20210129). The excellent news is that this one-shot vaccine candidate has efficacy against the variants present in Latin America and South Africa. Of note, Ad26.COV2.S demonstrated complete protection against COVID-19 related hospitalization (no ICU admission, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)) or death as of day 28 after vaccination.

These real-life data will now be confronted with in vitro studies of people aged 18-55 years who had received two 100 µg doses of mRNA-1273 vaccine which showed there was a 6-fold reduction in neutralizing titers against B.1.351 relative to prior variants. As these neutralizing titers remained above those previously found to be protective in non-human primate challenge studies, the producer of mRNA-1273 was confident that they would remain above levels that are expected to be protective (Moderna 20210125).

Recent research results might be less encouraging for monoclonal antibodies. B.1.351 has been shown to exhibit complete escape from three classes of therapeutically relevant monoclonal antibodies (Wibmer 2021). In another study, after examining the neutralizing effect of convalescent plasma collected from six adults hospitalized with COVID-19, Tulio de Oliveira, Alex Sigal and colleagues found that mutations in B.1.351 caused the virus to lose much of its sensitivity to antibodies, with IC50 6 to 200-fold higher relative to first-wave virus (Cele 2021). Finally, a study by David H. Ho and colleagues found that the serum of 12 people vaccinated with Moderna’s vaccine and 10 people vaccinated with the Pfizer-BioNTech vaccine was six to nine times less potent against B.1.351. Serum from 20 previously infected people was 11 to 33 times less potent (Wang P 2021). E484K accounted for much of the effect.

A piece of good news arrives from a group that found that a single shot of the Pfizer or Moderna mRNA vaccines boosts the neutralizing antibody response in people who were previously infected. Importantly, these antibodies also had neutralizing activity against the B.1.351 variant first detected in South Africa. The authors point to the importance of vaccination of both uninfected as well as of previously infected subjects (Statatatos 2021).

P.1

History and epidemiology

On January 6, 2021, the National Institute of Infectious Diseases (NIID) of Japan detected a new variant isolate of SARS-CoV-2 in isolates collected at airport screening from four travelers who arrived in Tokyo from Amazonas, Brazil, on January 2, 2021 at airport screening. The isolate had some mutations found in previously reported variant isolates of concern from the UK and South Africa (NIID 20210112). The new variant isolate had 12 mutations in the spike protein, including N501Y and E484K. A few days later, on 12 January 2021, a pre-print article described a variant detected in Manaus, Brazil, identical to the one detected in Japan (Faria 2021). The new variant, P.1, was identified in 42% (13 out of 31) of RT-PCR positive samples collected between 15 and 23 December in Manaus (Faria 2021). At the time, Manaus was experiencing an upsurge in COVID-19 cases.

As of 20 February, B.1.351 had been identified in 21 countries (Figure 25).

Figure 25. Map of P.1 local transmission, 5 February 2021 | Colours indicate reports of imported cases (pink) or of local transmission (darker purple). Data is obtained from news reports and similar sources and is manually maintained. Source and copyright: PANGO lineages, Áine O’Toole and Verity Hill, Rambaut Group, University of Edinburgh.

 

Virology

The new P.1 lineage carries 17 unique amino acid changes, 3 deletions, and 4 synonymous mutations, and one 4nt insertion compared to the most closely related available non-P.1 sequence (EPI_ISL_722052) (Faria 2021). P.1 has 11 amino acid changes in the spike protein compared to its ancestral lineage B.1.1.28 (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, H655Y, T1027I, and V1176F). Some mutations, such as E484K, N501Y and K417T, might influence antibody and vaccine efficacy. The variant is not closely related to B.1.1.7 or B.1.351.

The P.1 lineage and B.1.1.7 (first described in the UK – Rambaut 2020) share the spike N501Y mutation and a deletion in ORF1b (del11288-11296, 3675-3677 SGF). P.1 and B.1.351 (first described in South Africa – Tegally 2020) share three mutation positions in common in the spike protein (K417N/T, E484K, N501Y) (Faria 2021). Both the P.1 and the B.1.351 lineage also have the orf1b deletion del11288-11296 (3675-3677 SGF) (Faria 2021).

Another variant detected in Brazil, P2, is currently not considered a variant of concern. However, P2 is being intensely investigated because it has the E484K Spike and has been increasing in numbers since October (Fiocruz 2021).

Figure 26. Frequency of the main strains of SARS-Co-2 per month of sampling. Source and copyright: Fiocruz. http://www.genomahcov.fiocruz.br/frequencia-das-principais-linhagens-do-sars-cov-2-por-mes-de-amostragem/

Transmission

Manaus, the largest city in the Amazon region, has seen a dramatic surge in SARS-CoV-2 infettions since mid-December. As this coincides with a report of more than 40% RT-PCR positive P.1 samples collected between 15 and 23 December (Faria 2021), it is tempting to assume that the new variant has led to an increase in transmissibility of the virus. A previous pre-print paper claiming ‘herd immunity-like’ infection rates in September should be interpreted with caution (see the paragraph Acquired immunity, page 18).

Clinical consequences

At this stage, there is no clear evidence to suggest that P.1 has any impact on disease severity. A more precise picture will evolve within the next months.

Immune escape

As yet it is unclear if the mutation in the P.1 variant affects the ability of antibodies generated through a previous natural infection or through vaccination to recognize and neutralize the virus. In particular the presence of the mutation E484K could indicate a reduction in antibody neutralization (Greaney 2021, Greaney 2021b, Andreano 2020).

 

Manaus 2021

See also the paragraph Acquired immunity, page 18.

 

Galarraga Gortázar N, Schmidt S. La pesadilla de morir asfixiado en los hospitales de la Amazonia. El País 2021, published 24 January. Full-text: https://elpais.com/sociedad/2021-01-23/la-pesadilla-de-morir-asfixiado-en-los-hospitales-de-la-amazonia.html

Más de medio centenar de enfermos mueren sin aire en Manaos, mientras prolifera un mercado paralelo de oxígeno. Es un nuevo y terrible capítulo de la caótica gestión de la pandemia en el Brasil de Bolsonaro.

 

Brum E. Un estudio sostiene que Bolsonaro lideró una “estrategia institucional de propagación del virus”. El País 2021, published 23 January. Full-text: https://elpais.com/sociedad/2021-01-23/un-estudio-revela-que-bolsonaro-lidero-una-estrategia-institucional-de-propagacion-del-virus.html

Tras examinar 3.049 normas federales creadas en 2020, la Facultad de Salud Pública de la Universidad de São Paulo y la ONG Conectas Derechos Humanos analizan por qué Brasil supera las 212.000 muertes por covid-19.

 

Sampedro J. Vuelve Manaos. El País 2021, published 18 January. Full-text: https://elpais.com/ciencia/2021-01-18/vuelve-manaos.html

La primera ciudad que alcanzó la inmunidad de rebaño sufre de nuevo un aumento de casos.

 

Galarraga Gortázar N. Miles de brasileños siguen la decisión final sobre la vacuna en directo por YouTube. El País 2021, published 18 January. Full-text: https://elpais.com/sociedad/2021-01-17/miles-de-brasilenos-siguen-la-decision-final-sobre-la-vacuna-en-directo-por-youtube.html

Una enfermera negra recibe en São Paulo la primera dosis de inmunizante minutos después de que las dos inyecciones candidatas fueran aprobadas.

 

Schimidt S. Los hospitales de Manaos se quedan sin oxígeno en un segundo colapso sanitario por la pandemia. El País 2021, published 15 January. Full-text: https://elpais.com/sociedad/2021-01-15/los-hospitales-de-manaos-se-quedan-sin-oxigeno-en-un-segundo-colapso-hospitalario-de-la-pandemia.html

El Gobierno de Bolsonaro y el de Amazonas, que minimizaron la emergencia en Brasil, corren contra reloj para trasladar pacientes a otros Estados y conseguir importar el insumo.

 

Jucá B, Galindo J. Brasil llega a 200.000 muertes por coronavirus sin una estrategia clara de vacunación. El País 2021, published 8 January. Full-text: https://elpais.com/sociedad/2021-01-08/brasil-llega-a-200000-muertes-por-coronavirus-sin-una-estrategia-clara-de-vacunacion.html

Los picos de contagios son más moderados que en el inicio de la crisis, pero la pandemia se ha extendido por todo el territorio.

 

Galarraga Gortázar N. La falta de jeringuillas amenaza la vacunación contra la covid en Brasil. El País 2021, published 4 January. Full-text: https://elpais.com/sociedad/2021-01-03/la-falta-de-jeringuillas-amenaza-la-vacunacion-contra-la-covid-en-brasil.html

Este país, considerado un modelo en inmunización, no ha aprobado aún ninguna vacuna pese a sus casi 200.000 muertos por coronavirus.

 

Galarraga Gortázar N. Jair Bolsonaro celebra como un triunfo la suspensión del ensayo de la vacuna china. El País 2020, published 10 November. Full-text: https://elpais.com/internacional/2020-11-10/jair-bolsonaro-celebra-como-un-triunfo-la-suspension-del-ensayo-de-la-vacuna-china.html

El presidente de Brasil usa el asunto para redoblar su ofensiva contra el fármaco que promueve su rival João Doria, gobernador de São Paulo.

 

Galarraga Gortázar N. La caótica gestión lastra la batalla contra el virus en Brasil. El País 2020, published 19 May. Full-text: https://elpais.com/sociedad/2020-05-18/la-caotica-gestion-lastra-la-batalla-contra-el-virus-en-brasil.html

El boicoteo de Bolsonaro a las cuarentenas y la dimisión de dos ministros de Salud marca la respuesta a la pandemia en el tercer país con más casos y el sexto con más muertos.

 

Goulart J. Una médica de urgencias en uno de los epicentros de la pandemia en Brasil: “La gente muere sola, sola, sola.” El País 2020, published 3 May. Full-text: https://elpais.com/sociedad/2020-05-02/una-medica-de-urgencias-en-uno-de-los-epicentros-de-la-pandemia-en-brasil-la-gente-muere-sola-sola-sola.html

La doctora Uildéia Galvão relata desde Manaos las difíciles condiciones de trabajo y el colapso del sistema. Los profesionales no cobran desde febrero

 

Galarraga Gortázar N, Torrado S, Fowks J. Los indígenas de la Amazonia lanzan un SOS para reclamar protección ante la pandemia. El País 2020, published 6 May. Full-text: https://elpais.com/internacional/2020-05-06/los-indigenas-de-la-amazonia-lanzan-un-sos-para-reclamar-proteccion-ante-la-pandemia.html

Las primeras muertes y el avance de los contagios activan las alarmas en la frontera que comparten Brasil, Colombia y Perú.

 

B.1.429 (CAL.20C)

In California, the proportion of SARS-CoV-2 cases associated with this variant rose from 3,8% to 25% between mid-November and late December. By then, B.1.429 (CAL.20C) accounted for 24% of samples in one study, and 36,4% (66/181) of samples in a local Los Angeles cohort (Zhang W 2021). The emerging predominance of this strain is temporally related to the time of onset of the current spike in SARS-CoV-2 infections in Southern California. B.1.429 (CAL.20C) is defined by mutations in the S protein (L452R, S13I, W152C) and in the ORF1a (I4205V) and ORF1b protein (D1183Y).

Mutations

Do you know “what mutations define a variant, what impact they might have (with links to papers and resources), and where variants are found”? If you don’t, the excellent web site https://covariants.org, by Emma Hodcroft et al., will provide you a primer (Figure 27).

Figure 27. Overview of variants in countries. The graphs show for each country, the proportion of total number of sequences (not cases), over time, that fall into defined variant groups. Source and copyright: CoVariants.org, by Emma Hodcroft et al.

 

E484K (“Eric”)

E484K is the mutation that could have the largest effect on antibody-binding and neutralization (Greaney 2021b). Find more information at CoVariants.org: https://covariants.org/variants/S.E484.

N501Y (“Kelly”)

Overview at https://covariants.org/variants/S.N501.

N439K (“Nick”)

Overview at https://covariants.org/variants/S.N439K.

Q677P / Q677H

Emma Hodcroft et al. described 7 newly identified coronavirus variants in the US with a mutation in spike position 677 (also named after birds, Mockingbird to Yellowhammer) (Hodcroft 2021). The authors recommend keeping an eye on S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility. Find more at https://covariants.org/variants/S.Q677.

Prevention and Care

In the coming months, the new SARS-CoV-2 variants will confront many countries with a novel wave of viral spread. Once a more contagious variant has established itself, stabilizing the number of new infections will become increasingly difficult (Priesemann 2021), leading to a spiral of increasing number of infections, hospitalisations and deaths. The increased transmissibility of SARS-CoV-2 variants has far-reaching public health consequences. Non-pharmaceutical interventions (NPIs = everything from mask wearing to lockdowns) which were sufficient to control previous SARS-CoV-2 lineages may need to be reinforced to control B.1.1.7, B.1.351 and P.1. Fortunately, as shown in the Epidemiology section above (page 5), hard lockdowns, including closing of primary schools, secondary schools, and universities (Davies 2020) are effective against new variants. In the future, wastewater analyses may help predict outbreaks with new variants. In Switzerland, a group found evidence for the presence of several mutations that define B.1.1.7 and B.1.351 in a sample from a Swiss ski resort dated around mid-December, two weeks before its first verification in a patient sample in the country (Jahn 2021).

Since the population groups driving transmission will not be targeted with vaccination for some months, ECDC recommends that Member States should to be very cautious about relaxing currently enacted NPIs. Non-essential travel should be avoided. Vaccination should focus on protecting those most at risk from severe disease. Find an overview of Options for response in ECDC’s Rapid Risk Assessment (ECDC 20210121, page 15), in particular

  • Surveillance, testing and detection of the emering variants
  • Non-pharmaceutical interventions
    • Community measures
    • Shielding medically and socially vulnerable populations
    • Considerations for school settings
    • Contact tracing for emerging variants
    • Measures for travellers
  • Vaccination
    • Availability of COVID-19 vaccines
    • Monitoring breakthrough infections following vaccination, adjustment of vaccination schedules and possible update of vaccine contents due to SARS-CoV-2 variants in circulation
    • Accelerating vaccination campaigns
    • Vaccine effectiveness studies
  • Hospital and healthcare preparedness

 

These recommendations translate into 9 commandments: “Whenever possible:

  1. Stay home, if you can
  2. Avoid gatherings, both inside and outside your household
  3. Avoid enclosed spaces
  4. Wear a mask, do not sing or shout!
  5. Keep a distance – 2 meters!
  6. Ventilate whenever you can
  7. Wash hands
  8. Disinfect hightouch surfaces (maybe less important?)
  9. Get vaccinated as soon as you can!”

 

Or, according to the more joyful words of UN Women: “The pandemic is hard – spread joy:

  • Buy someone flowers
  • Call a loved one
  • Deliver groceries to your neighbour
  • Write a greeting card
  • Motivate a friend who needs a boost
  • Virtually tutor a student
  • Make face masks to give away”

Outlook

In a few months, we will learn more about whether and how B.1.1.7, B.1.351 and P.1 will

  • Change the clinical presentation of COVID-19 and mortality
  • Affect the few existing treatment option (corticosteroids, tocilizumab, anticoagulants, etc.)
  • Increase the number of reinfections
  • Affect the immune response to vaccines
  • Affect the therapeutical benefit from monoclonal antibodies

Fortunately, global genomic surveillance and rapid open-source sharing of viral genome sequences have facilitated near real-time detection, comparison, and tracking of evolving SARS-CoV-2 variants that can inform public health efforts to control the pandemic (Galloway 2020).

Vaccine producers are already at work. Pfizer-BioNTech and Moderna are modifying their vaccine for emerging variant booster candidates. They will test an additional (third) vaccine booster dose to study if neutralizing titers against emerging variants can be increased. All companies have started talks with regulators to know what types of clinical trials and safety reviews would be required to authorize new versions of already approved vaccines. Over time, it is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would give rise to continual reformulation of existing vaccines (Kistler 2021).

We expected 2021 to the year of the SARS-CoV-2 vaccine. We didn’t expect it to be the year of a race between the virus and SARS-CoV-2 vaccines. Vaccines – and science – will ultimately prevail, but for the coming months, the race will stay close. When the COVID waters calm down in a year or so, we should not stop thinking about infectious diseases. The next pathogen to emerge might be less accommodating (Burton 2021) and we should start thinking about a rational vaccine design based on broadly neutralizing antibodies (Burton & Topol 2021). Creating the tools for preventing the next coronavirus pandemic is within our power and should be considered a global health priority. We can either invest now or pay substantially more later (Koff & Berkley 2021).

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