All viruses are always mutating and they change their form as they move from one person to another.

True to its nature, the new coronavirus is also mutating, albeit slowly, unlike the influenza virus, which mutates very rapidly. “The more opportunities a virus has to spread, the more it replicates – and the more opportunities it has to undergo changes”, says the World Health Organisation (WHO).  Some mutations are favorable to the virus enabling it to become either more transmissible and/or more virulent and create new variants of interest (VOI) and variants of concern (VOC), while others die out.

Last year, a SARS-CoV-2 variant carrying the Spike protein amino acid change D614G in the ancestral virus was the most prevalent form globally. More new lineages of the novel coronavirus since then have been identified and were recently renamed by the WHO. The B.1.1.7 -  now named as Alpha (first detected in the United Kingdom), B.1.351 - now named as Beta (first identified in South Africa), P.1-  now named as Gamma (first detected in Brazil) and the B.1.617 variant - now named as Delta  (first detected in India).

The B.1.617 variant has three sublineages – B.1.617.1, B.1.617.2 and B.1.617.3. It is the B.1.617.2 sublineage, which has been named as the Delta variant. The B.1.617.1 strain, named Kappa has been categorised as VOI, while the B.1.617.3 lineage is “no longer classified as either a VOI or VOC” and is being monitored. Early data from INSACOG, a consortium of 10 National Laboratories shows that B.1.617.2 has higher transmission advantages over the other two sublineages. The Delta variant, also called the double mutant variant as it has two mutations E484Q and L452R, originated in India in Maharashtra in Vidarbha region in October 2020 and then spread to the rest of the country and then to other countries as well. It is the most prevalent strain in India.

The delta variant is highly infectious. It tends to cause more pneumonia because of its greater affinity to the ACE2 receptors in the lungs. The delta variant has greater immune escape and reinfection properties. The risk of hospitalisation is doubled, particularly in people with comorbid conditions. Data from the UK Zoe Covid Symptom Study show a change in the presenting symptoms. Headache, sore throat, runny nose, akin to a “bad cold” are now more common, while symptoms like cough and loss of smell that were prevalent in the first wave are becoming uncommon.

The deadly second wave in the country, which caused significant morbidity and mortality, was predominantly due to the delta strain. An NCDC (National Center for Disease Control) report has shown that the delta variant accounted for almost 100% of Covid cases in Madhya Pradesh in June. In April, this number was 57%, which increased to 69% in May.

It is quickly spreading around the world and has overtaken the alpha variant to become the dominant variant globally. Almost 100 countries have reported the delta variant rightly making it the fourth strain to be declared a VOC (May 11, 2021) due to evidence of increased transmissibility. The increase in the effective reproduction number compared with the Alpha variant is estimated to be 55% (WHO). In the UK, the delta variant accounts for 99% of sequenced and genotyped cases across the country.

Delta Plus, an emerging VOC

The delta variant has undergone a new mutation (K417N) in the spike protein to form a new variant, called the Delta Plus or AY.1, which is found in India, UK, Nepal and other countries. Another lineage of the delta variant is AY.2, which is found in California. The Delta Plus variant was first identified in India on June 11. It was declared a VOC by the Health Ministry on June 22. At least 12 states have reported Delta Plus cases. Delhi which had seen an exponential rise in the number of cases in the second wave so far has not detected any case of the Delta plus variant. But this could soon change. Globally, more than 12 countries have detected Delta Plus cases.

Preliminary research has shown that the K417N mutation affords “immune escape” properties to the variant. There is an apprehension that the Delta Plus could be a key driver of the impending third wave in the country. The reasons for this concern are its three characteristics namely, increased transmissibility, stronger binding to ACE2 receptors in the lung and potential reduction in response to monoclonal antibodies. As of now, around 51 cases of the variant have been detected in the country from 45,000 samples that were tested as reported. However, early analysis does not substantiate this from India. More data is needed before it can be said that the delta plus variant would significantly contribute to the third wave, if and when it comes.

Do current vaccines protect against VOCs in India?

Post-vaccine breakthrough infections are being reported even in fully vaccinated individuals. While non-adherence to Covid-appropriate behavior definitely has a role to play in this, there is no denying the role of the emerging variants of concern in reinfections.

The major VOCs in India are the B.1 (the first lineage of ancestral Wuhan virus also called G614), alpha variant and delta variants. Few cases of Beta and Gamma variants have also been reported in the country.

Covaxin (BBV152) is manufactured using the original ancestral variant G614 (virus strain (NIV-2020-770) containing the Asp614Gly mutation). The virus was captured from a Covid patient to ensure that pathogenetic virus is used for manufacturing vaccine. It was further grown on Vero cell lines and chemically inactivated. Covishield, the ChAdOx1 nCoV-19 vaccine (AZD1222) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the gene for (early) spike protein, nCoV-19.

In a study conducted by the Public Health England and reported as a preprint (MedRxiv. May 24, 2021) by Jamie Lopez Bernal, et al, the Pfizer and AstraZeneca Covid-19 vaccines are effective against symptomatic disease due to the B.1.617.2 variant.

• The two doses of the Pfizer vaccine showed 87.9% efficacy in preventing symptomatic disease due to the B.1.617.2 variant, while the two doses of the AstraZeneca vaccine demonstrated 59.8% efficacy against the B.1.617.2 variant.
• This study also demonstrated 93.4% efficacy against B.1.1.7 with two doses of Pfizer vaccine vs 66% efficacy with two doses of the AstraZeneca vaccine.
• But, the effectiveness after single dose of both vaccines was only 33%.

According to the authors, “These findings suggest a modest reduction in vaccine effectiveness. Nevertheless, a clear effect of both vaccines was noted with high levels of effectiveness after two doses.” This study clearly highlights the need to take both doses of the vaccine.

The vaccines available in the country, Covishield and Covaxin work against the four VOCs.

A study by the National Institute of Virology (NIV) examining the efficacy of two doses of BBV152 (Covaxin) against the variants confirmed a reduction in neutralization titers with sera of Covid-19 recovered cases (3.3-fold and 4.6-fold) and BBV152 vaccinees (3. 0 and 2.7 fold) against B.1.351 and B.1.617.2 respectively. Despite reduction in neutralization titer, Covaxin demonstrated protective response against VOC B.1351 and B.1.617.2 (BioRxiv, June 7, 2021). Recently, the NIH has acknowledged the efficacy of Covaxin against the delta variant.

So, will a booster dose of the current vaccines help to increase the levels of antibodies?  A Nature study (published June 28, 2021) observed that the mRNA vaccines generated a strong immune reaction, which may be protective against coronavirus for years. Another study had previously reported that people who have recovered from infection and then had been fully inoculated with any mRNA vaccine have an even stronger immune response with high levels of neutralizing antibodies that were effective against the coronavirus and its variants. These studies suggested that such individuals may not need a booster dose, provided that the virus did not mutate further. 

SARS-CoV-2-directed antibodies have been shown to persist for more than six months in patients with mild to moderate Covid-19 (Infection. 2021 Mar 10:1–8). Once antibody titers decline, T cell mediated response take on. SARS-CoV-2-specific T cell immunity is long-lasting in the majority of convalescent individuals (BioRxiv, November 16, 2020)

Preliminary results from the phase 2 CombivacS clinical trial in Spain of more than 600 participants show that mixing and matching Covid vaccines – Oxford/AstraZeneca and Pfizer/BioNTech - produces a strong immune response against SARS CoV-2 indicating that the heterologous vaccine regime is highly immunogenic and safe. Adverse effects are mild to moderate and similar to what is expected with homologous vaccine regimes. It is pertinent to point out here that India does not recommend mixing and matching of Covid19 vaccines.

Effectiveness of the vaccines available in India against the Delta Plus variant is being tested in ongoing trials and the results are expected soon.

The Answer

The new variants of the coronavirus are highly transmissible. The Delta variant is around 60% more transmissible than the Alpha variant (which was earlier the dominant variant) and causes more severe disease. Aggressive vaccination appears to be the only answer to stop this relentless march of the virus. Any complacency on our part will surely usher in the third wave.

However, correct and consistent use of masks (triple layer) and adherence to Covid-Appropriate behavior continue to be as important as before for everyone even the fully vaccinated persons, perhaps even more now, as more new variants may still emerge. Herd immunity will remain an elusive goal, until everybody eligible takes the vaccine.

”Double Mask and Vaccinate” is the key for India to make it Covid-free in the future.