“In fact, biology is chaos. Biological systems are the product not of logic but of evolution, an inelegant process. Life does not choose the logically best design to meet a new situation. It adapts what already exists ... The result, unlike the clean straight lines of logic, is often irregular, messy.”

— John Barry, The Great Influenza: The Story of the Deadliest Pandemic in History

As we cross the 1.5-year mark on the Covid-19 pandemic, finally armed with vaccines, permanent reprieve eludes us. New waves of infection keep erupting in various parts of the world. While there are many factors at play, a major perpetrator of this stuttering apocalypse is the emergence of variant strains of the virus.

With new variants and new information (and misinformation) coming out, it can be overwhelming to try and keep up. Here we attempt to answer some questions about the variants, and what they mean for the world and Pakistan.

How and why do variants emerge?

Like all viruses, SARS-CoV2, the virus that causes Covid-19, is evolving over time. These changes are brought on by an imperfect replication mechanism that leads to minute changes in the genetic structure of the virus every time it replicates. Most of these changes have little impact on the resultant mutant; they may even cause the mutant to become ineffective and die off. But once in a while, a mutant wins the genetic lottery and gains a property that either confers increased infectivity with a greater ease of attachment to host, or escape from vaccines or therapeutics that leads to the rapid spread of this rogue variant.

With new variants emerging, keeping updated with reliable information can feel overwhelming. Three doctors answer your questions

To continue the lottery analogy, the more lottery tickets you buy, the higher your chances of winning. In the same way, the more chances the virus has to replicate (ergo the number of new or active infections) is directly related to the probability of emergence of a new variant. In short, Covid-19 clusters, anywhere in the world, are breeding grounds for new, and possibly deadly, variants.

How are variants classified?

Since the beginning of the pandemic, the World Health Organisation (WHO) has been tracking the evolution of the SARS-CoV2 virus. The WHO currently classifies variants of significance into two broad categories.

Variants of Interest (VOI): Variants that have genetic changes that are predicted to change viral characteristics towards increased transmissibility, virulence and therapeutic escape; have had multiple Covid-19 clusters in multiple countries; and pose a global public health risk.

Variants of Concern (VOC): Variants of interest that, through rigorous assessment, have been found to have one or more of the following characteristics and cause concern at a global public health scale. Increased transmissibility, increased virulence, diagnostic/therapeutic escape.

Moreover, WHO has laid special emphasis on ensuring that the nomenclature of variants is easy to pronounce, for ease of public engagement and non-stigmatising against any ethnicity or country.

The accepted international nomenclature for public reporting is based on Greek letters (Alpha, Beta, Gamma etc).

Significant variants

Alpha: Among the first identified variants of the SARS-CoV2 virus was the Alpha variant. Discovered in the UK in September 2020, the Alpha variant was responsible for the surge of infections last winter in the UK and, according to WHO’s July 6, 2021, weekly epidemiological update, has subsequently spread to 173 countries thus far (1). The Alpha variant has an approximately 50 percent increased transmissibility over the wild type SARS-CoV2 virus, and studies show increased mortality and hospitalisations when compared to other Covid-19 cases (2). It is a designated a VOC by the WHO.

Beta: Discovered earlier than the Alpha variant (May 2020), with first cases isolated from South Africa. Just like Alpha, the Beta variant is associated with roughly 50 percent increased transmissibility and, according to the Centres for Disease Control and Prevention (CDC), has also been found to be more resistant to monoclonal antibodies (3) — a treatment used widely in healthcare, especially in the Western hemisphere. This variant has so far been reported in 122 countries. It was also designated as a VOC by WHO in December 2020.

Gamma: Initially discovered in Brazil in November 2020 and was subsequently designated as a VOC in January 2021. This variant had a major role in overwhelming the healthcare system of Brazil, leading to an oxygen shortage (4). According to the CDC, this strain has also demonstrated increased resistance to monoclonal antibodies and convalescent plasma (5), with an increased risk of reinfection (6). So far, the Gamma variant has been reported in 74 countries (7).

Delta: Isolated in India in October 2020, was initially designated as a VOI in April 2021 and was subsequently changed to a VOC in May 2021. The Delta variant has been observed to have a 50 percent transmissibility advantage over the Alpha variant and has almost double the transmissibility of the wild type (8), making its transmissibility comparable to smallpox. So far, this variant has been reported in 104 countries and, with the increased transmissibility, is the predominant variant in the US and projected to account for more than 90 percent of the Covid-19 cases in Europe by August 2021 (9).

Other variants found and designated as VOIs by WHO are beyond the scope of this article.

According to the latest weekly epidemiological update by the WHO (6 July, 2021), Pakistan has a reported presence of all four of the VOC. The presence of variants was also confirmed by the National Command and Operations Centre (NCOC).

Variants in Pakistan

According to the latest weekly epidemiological update by WHO (July 6, 2021), Pakistan has a reported presence of all four of the VOCs (10). The presence of variants was also confirmed by the National Command and Operations Centre (NCOC) (11). However, publicly available, reliable, information on the proportions of each strain in Pakistan could not be found by these authors.

Some estimates suggest the Alpha variant as being the dominant variant in Pakistan as late as May 2021 (12). So far, Pakistan has experienced three significant waves of Covid-19 infections; with the first wave starting in spring of 2020 and single-day infection rates as high as 6,500, the second wave in fall 2020 and daily infection rates peaking at 3,200; and the third wave in Spring 2021 with a daily peak-infection rate at roughly 5,700 (13). With the Delta variant right at our doorstep and wreaking havoc in our neighbourhood, a fourth wave may be looming over us.

Variants and vaccine efficacy

As the SARS-CoV2 virus keeps evolving and new variants keep emerging, there have been growing concerns regarding the development of resistance against existing vaccines, a phenomenon called vaccine escape.

A recent study on SARS-CoV2 viral genetics from Michigan State University concludes that recent mutations arising in the virus not only show a trend towards better binding with human receptors, leading to increased infectivity, but also decreased affinity for neutralising antibodies produced by our body, decreasing the efficacy of existing vaccines (14).

The same study also reports mutation in the genome of Beta, Gamma and Delta variants that can potentially disrupt the binding of neutralising antibodies, leading to vaccine escape. Whether these genetic changes translate to actual vaccine escape in the real world remains to be seen.

While the information regarding the efficacy of different vaccines against SARS-CoV2 variants is in constant flux, preliminary data shows all major vaccines including Pfizer, Moderna, AstraZeneca, Johnson & Johnson, Sputnik V, Sinopharm and Sinovac-Coronavac are reasonably effective against, at least, severe infections and bad outcomes (hospitalisation and death) (15).

However, newer variants have been found to be more resistant to vaccines with regards to symptomatic infections and neutralising antibody response. To curtail this vaccine resistance and, in anticipation of potential vaccine escape, multiple strategies are at play internationally. Vaccine manufacturers are working towards booster doses of vaccines to mount a more robust immune response, with some boosters targeted against new variants (16). Another strategy, currently being evaluated, is mixing-and-matching vaccines from different manufacturers. Multiple studies are underway to test different combinations of vaccines, and the preliminary data shows promising results (17).

What is the WHO’s stance on vaccine equity?

In light of the lack of definitive evidence of efficacy of all available vaccines against the newly emerging variants, many Western countries took an aversive stance against Russian and Chinese vaccines (18), with easing of travel restrictions only for people vaccinated with ‘Western vaccines’.

Other countries such as Singapore took a more nuanced approach: while they did not include residents vaccinated with SinoVac-CoronaVac to the tally of their vaccinated population, they did encourage SinoVac-CoronaVac uptake by their citizens, with their Health Minister Ong Ye Kung saying taking the vaccine “contributed to the resilience” of the community (19).

However, WHO was fast to rebuke this differential treatment of some vaccines with a joint Covax statement on the issue (20). According to the statement, any differential treatment of people protected by one vaccine versus the other will lead to a widening of the, already huge, chasm between the resource-rich and resource-limited parts of the world, and deepen vaccine inequities.

Having reviewed the clinical data available on all the vaccines, these authors believe that the inactivated SARS-CoV2 vaccines such as Sinopharm are significantly effective. And we, therefore, endorse WHO’s stance: all vaccines that have been deemed safe and effective by the World Health Organisation… should be treated as equal “when making decisions on who is able to travel or attend events” (21).

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(1) https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---6-july-2021

(2) Davies, Nicholas G.; Abbott, Sam; Barnard, Rosanna C.; Jarvis, Christopher I.; Kucharski, Adam J.; Munday, James D.; et al. (9 April 2021). "Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England". Science. 372 (6538): eabg3055. doi:10.1126/science.abg3055

Challen, Robert; Brooks-Pollock, Ellen; Read, Jonathan M.; Dyson, Louise; Tsaneva-Atanasova, Krasimira; Danon, Leon (10 March 2021). "Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study". BMJ. 372: n579. doi:10.1136/bmj.n579. ISSN 1756-1833. PMC 7941603. PMID 33687922

Davies, Nicholas; Jarvis, Christopher; CMMID COVID-19 Working Group; Edmunds, W. John; Jewell, Nicholas; Diaz-Ordaz, Karla; Keogh, Ruth (15 March 2021). "Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7". Nature. 593 (7858): 270–274. Bibcode:2021Natur.593..270D. doi:10.1038/s41586-021-03426-1. ISSN 1476-4687. PMID 33723411

Statens Serum Institut (24 February 2021). "B.1.1.7 kan føre til flere indlæggelser" [B.1.1.7 might lead to more hospital admissions] (in Danish). Retrieved 25 February 2021

Patone M, Thomas K, Hatch R, Tan PS, Coupland C, Liao W, Mouncey P, Harrison D, Rowan K, Horby P, Watkinson P, Hippisley-Cox J. Mortality and critical care unit admission associated with the SARS-CoV-2 lineage B.1.1.7 in England: an observational cohort study. Lancet Infect Dis. 2021 Jun 22:S1473-3099(21)00318-2. doi: 10.1016/S1473-3099(21)00318-2. Epub ahead of print. PMID: 34171232; PMCID: PMC8219489.

(3) https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html

(4) https://www.bloomberg.com/news/articles/2021-01-15/brazil-scientists-see-signs-of-new-virus-mutations-amid-outbreak

(5) https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.htm

(6) https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---6-july-2021

(7) https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---6-july-2021

(8) https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---6-july-2021

https://twitter.com/larrybrilliant/status/1408948519390519296?refsrc=twsrc%5Etfw%7Ctwcamp%5Etweetembed%7Ctwterm%5E1408948519390519296%7Ctwgr%5E%7Ctwcon%5Es1&ref_url=https%3A%2F%2Ffortune.com%2F2021%2F07%2F08%2Falpha-delta-lambda-covid-variant%2F

(9) https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---6-july-2021

(10) https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---6-july-2021

(11) https://www.dawn.com/news/1633591

(12) https://www.reuters.com/world/asia-pacific/uk-variant-accounts-70-covid-cases-pakistan-researcher-2021-05-08/

(13) https://ourworldindata.org/coronavirus/country/pakistan

(14) Rui Wang, Jiahui Chen, Kaifu Gao, Guo-Wei Wei, Vaccine-escape and fast-growing mutations in the United Kingdom, the United States, Singapore, Spain, India, and other COVID-19-devastated countries, Genomics, Volume 113, Issue 4, 2021, Pages 2158-2170, ISSN 0888-7543, https://doi.org/10.1016/j.ygeno.2021.05.006.

(15) https://www.nejm.org/doi/full/10.1056/NEJMc2104974

https://www.beckershospitalreview.com/public-health/how-vaccines-stack-up-against-cdc-s-5-variants-of-concern.html

Effectiveness of COVID-19 vaccines against variants of concern, Canada Sharifa Nasreen, Siyi He, Hannah Chung, Kevin A. Brown, Jonathan B. Gubbay, Sarah A. Buchan, Sarah E. Wilson, Maria E. Sundaram, Deshayne B. Fell, Branson Chen, Andrew Calzavara, Peter C. Austin, Kevin L. Schwartz, Mina Tadrous, Kumanan Wilson, Jeffrey C. Kwong medRxiv 2021.06.28.21259420; doi: https://doi.org/10.1101/2021.06.28.21259420

Effectiveness of COVID-19 vaccines against the B.1.617.2 variant Jamie Lopez Bernal, Nick Andrews, Charlotte Gower, Eileen Gallagher, Ruth Simmons, Simon Thelwall, Julia Stowe, Elise Tessier, Natalie Groves, Gavin Dabrera, Richard Myers, Colin Campbell, Gayatri Amirthalingam, Matt Edmunds, Maria Zambon, Kevin Brown, Susan Hopkins, Meera Chand, Mary Ramsay medRxiv 2021.05.22.21257658; doi: https://doi.org/10.1101/2021.05.22.21257658

mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants Kai Wu, Anne P. Werner, Juan I. Moliva, Matthew Koch, Angela Choi, Guillaume B. E. Stewart-Jones, Hamilton Bennett, Seyhan Boyoglu-Barnum, Wei Shi, Barney S. Graham, Andrea Carfi, Kizzmekia S. Corbett, Robert A. Seder, Darin K. Edwards bioRxiv 2021.01.25.427948; doi: https://doi.org/10.1101/2021.01.25.427948

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https://www.who.int/news-room/feature-stories/detail/the-sinovac-covid-19-vaccine-what-you-need-to-know

https://www.nejm.org/doi/full/10.1056/NEJMoa2107715?query=featured_coronavirus

(16) https://www.nytimes.com/live/2021/07/08/world/covid-19-vaccine-coronavirus-updates

(17) https://www.nature.com/articles/d41586-021-01359-3

https://www.nature.com/articles/d41586-021-01805-2

(18) https://www.nytimes.com/2021/02/05/opinion/covid-vaccines-china-russia.html

(19) https://www.channelnewsasia.com/news/singapore/sinovac-vaccine-covid-19-recipients-national-count-evidence-data-15172472

(20) https://www.who.int/news/item/01-07-2021-joint-covax-statement-on-the-equal-recognition-of-vaccines

(21) https://www.who.int/news/item/01-07-2021-joint-covax-statement-on-the-equal-recognition-of-vaccines

Dr Muhammad Ali Chaudhary, MD is a physician-scientist and Family Medicine resident at Wellspan Health, Pennsylvania. He is a former Health Services Research Fellow at Brigham & Women’s Hospital, Harvard Medical School

Dr Usman T. Malik, MD is a physician-writer and Assistant Professor at Shalamar Medical & Dental College, Lahore, as well as the University of Central Florida

Dr Abdul Waheed, MD is a physician-scientist, Associate Professor, and the Program Director of Family Medicine Residency at Wellspan Good Samaritan Hospital, Pennsylvania, USA

Published in Dawn, EOS, July 18th, 2021