Topic: Covid-19 variants, recombinants and way forward

Speaker: Prof Shashank Joshi, Endocrinologist, Joshi Clinic, Lilavati Hospital, & Bhatia Hospital, Mumbai; Member, Covid-19 Maharashtra State Task Force

9^th April, 2022, Saturday, 9.30-10.30am 

• As the omicron wave is receding, across the world there has been a concern and fear of recombinants. 
• The world is divided into two camps: the Inevitability camp and the Avoidance camp. 
• The inevitability camp says that the Omicron wave was mild, lung to lung cell virulence is mild and the  vaccine and/or infection induced T cells hold up well and protect from severe disease. Booster shot is immaterial because it will last only up to 3 months. We cant worry about long covid, we dont need antivirals and probably we can get over all this because we have hybrid immunity. 
• But there is the avoidance camp, which says that disease is less severe and mild is not always mild. It is a big concern even now in the US and Europe. Even today we are losing people who are immunocompromised, aged because we do not have an assured layer of defence. The precaution doses are helpful but despite four doses we are getting breakthrough infections and we are getting debilitating long covid across the world. Medical supplies like antivirals are limited. The highly transmissible newer strains particularly BA.1 and BA.2 are definitely around the corner. They are more contagious and transmissible. 
• The omicron strain (BA1.1.529) was detected in November 2021; it grew out from alpha, beta and the gamma variants, which were totally replaced by the delta strain. It has the highest transmissibility, lower disease severity and highest immune escape from previous infections.
• This strain was mainly discovered in South Africa and Hongkong between November 11 and November 23 with more than 30 mutations in the spike protein alone. It has 10 mutations on the ACE2 receptor (the beta variant has 3 and the delta variant has 2 mutations). It has S gene target failure, but the initial BA.1 strain was rapidly overtaken by the BA.2 strain, which did not have S gene target failure.
• Omicron is now the dominant strain in the world and has replaced the delta variant, which was lethal and virulent. It is rapidly transmissible, supermutant strain with more than 50 mutations; it has immune escape; breakthrough infections are common, but the severity and virulence of omicron are less severe whether it is BA.1, BA.2 or BA.3. The BA.2 is causing havoc around the world.
• The number of mutations in delta are sparse but they are plenty in omicron. But the global fear is that if these two strains combine, we will get a deadly recombinant strain, which has been popularly called as deltacron, which created huge fear.
• Most of the reportages in last 3-6months were predominantly linked to probably contamination they were called recombinants.
• The monoclonal antibodies which work now have moved away from the traditional casirivimab and imdevimab to sotrovimab and tiglivimab and the newer upcoming molecules.
• Covid therapy today is all about immune boosting through vaccines. neutralising monoclonal antibodies of different types, immune modulators like steroids, IL-6 blockers and antivirals like molnupiravir, paxlovid or remdesivir. But the focus clearly is on no deaths, less severity of disease and mild to moderate disease.
• When two related viruses infect the same cell i.e., during a coinfection, the viral replicating machinery can accidently switch from genome to other resulting in a mixed genome. This is viral recombination.
• SARS-CoV-2 has been doing this all through the pandemic. However, it is easy to see when the two parental viruses are distantly related e.g., alpha or prevariant. Therefore, the reason we are seeing lots of recombinants is as until recently we had lots of genetically distinct viruses in circulation such as delta, BA.1 and BA.2. When recombination occurs between these lineages, it is possible to identify, even if the switched part of the genome is small. 
• All this was highlighted because UK and Europe do a lot of genome sequencing. When BA.1 took off in Europe and USA, there was a very high delta wave already circulating. So, when BA. 1 Omicron came, there were huge opportunities for coinfection, recombination and transmission going onwards.
• The new recombinant lineages fall in two categories: Delta x BA.1 (referred to as deltacron in the media) and classical recombination of BA.1 x BA.2, which is now being described in the UK.
• XD is the new recombinant lineage; it the new name for the French delta x BA.1 lineage sequenced at the Pasteur Institute. It contains the spike protein of BA.1 and the rest of the genome from delta. It currently comprises of several 10s of sequences; possibly more transmissible, but virulence is unknown.
• The XE is a large UK BA.1 x BA.2 lineage. It was sequenced and verified by the UKHSA and the Wellcome Sanger Institute. It has the spike and structural proteins from BA.2 but the 5’ part of its genome is from BA.1. At present, it comprises several hundred sequences.
• The XF is a UK delta x BA.1 lineage. It was also sequenced by the UKHSA. It has the spike and structural proteins from BA.1 but the 5’ part of its genome is from delta. At present, it comprises several tens of sequences.
• The UK currently uploads around 10x more sequences than France. Therefore, 10s of sequences in France are roughly equivalent to 100s of sequences from the UK.
• Recombinants that contain the spike and structural proteins from a single virus (such as XE or XF) are fairly likely to act similarly to their parental virus. So, there is no major fear or concern.
• All these recombinants, including smaller clusters that have not been assigned, should be closely monitored for signs of growth and attempts should be made to isolate and characterize where possible.
• Recombinants are here to stay. They are more transmissible, but may be less virulent. Immune escape is another challenge with recombinants.
• India had a delta wave from April to May and the omicron wave from mid-December to end of January. There has been a large exposure to infection naturally. Also, 190 Cr of Indians have been vaccinated. Hence, the Indian population is likely to have hybrid immunity. Therefore, the probability of a fourth wave which may disrupt the country is less likely in the next 3-6 months. Hybrid immunity is the best immunity. We need hybrid immunity across the world.
• As of date, Covid is still predictably unpredictable. The only overarching feature in the way forward is to save lives. Behave responsibly, preferably mask if in crowded closed spaces and get your vaccination on schedule. 
• The immunocompromised, elderly, those with lot of comorbidities are still at risk. Covid can still kill in this vulnerable group. 
• The threat of recombinants is real. But they are not likely to pose a major threat in the near future.
• We need to look into alternative routes of vaccine delivery &vaccine platforms. Nasal vaccines could be effective. In India, one nasal vaccine is under research and trial.
• The m-RNA was a robust platform good for spike protein but it has limitations.
• Hybrid immunity - vaccine-induced as well as natural acquired immunity is going to play a key role in times to come as we live with covid. But we have to protect our vulnerable population.
• Waves will keep on coming and going. We hope that even if transmissibility goes up, virulence should come down. We need to have incremental innovation on vaccine platforms, vaccine route of delivery and have better neutralization capabilities as new strains and recombinants will come. 

#2. Country Updates

• South Africa: In the last 24 hours there were 1377 new cases and 9 deaths. Active cases are 12,358; the recovery rate is 97%; positivity rate last week was between 6 and 6.8. Across the country, 2138 were admitted to hospitals, both private and public; of these, 161 in ICU, 62 on ventilator. Vaccination rate is 34 million; it has plateaued. Scientists have warned that there may be another wave in May this year. So, the situation is being monitored. 
• India Update: The number of cases is coming down. Yesterday there were 1000 odd cases. Total patients with covid are 10,000 or so. Immunization is strong; 187 crore vaccine doses have been given. Booster dose is now extended to all persons above 18 years of age. All restrictions have been withdrawn except Covid appropriate behavior i.e., mask wearing and hand washing. There has been a marginal increase in cases in states where mask wearing has been made optional. Two cases of XE have been identified in India: one in Maharashtra, which is yet to be confirmed and one confirmed case in Gujarat. 
• USA Update: In the US, both BA.1 and BA.2 strains are prevalent. The state of Wisconsin has 25% BA.2 and 75% BA.1; there is no XE strain. There has been a very strong wish for relaxing social distancing, masking mandates and there has been an increase in spread. In April, case counts are low. In a study from Israel regarding the 4th dose of vaccine, there was a four-fold decrease in severity of the disease at 6 weeks and 2-fold decrease in the rate of infection. This week CDC released guidelines for 4th dose. Those who are 12 years & old and immunocompromised & those who are 50 years old and older and not moderately to severely immunocompromised can get their 2nd mRNA booster dose. Those (18-49 years) who have taken the J&J vaccine are also eligible for their 2^nd booster dose with mRNA vaccine. Annual influenza vaccine starts from September.

Participants

Member National Medical Associations

Dr Marthanda Pillai, India Member World Medical Council, Advisor CMAAO

Dr Mvuyisi Mzukwa, South Africa

Dr Angelique Coetzee, South Africa

Dr Akhtar Hussain, South Africa

Invitees

Dr Monica Vasudev, USA

Dr Shashank Joshi, India

Dr Patricia La’Brooyi

Dr EC Ng

Dr Blan Lee

Dr Chia Ai Mian

Dr Hamid Ahmad

Dr Kathleen Su Meng Yp

Dr Ng Hwee Hin

Dr S Sharma, Editor IJCP Group

Moderator

Mr Saurabh Aggarwal