Vaccine breakthroughs

May 8, 2021 0 By S Harachand

Even as India is trying out various models to fine-tune and scale up its vaccination strategy, more and more cases are coming up involving re-infections and breakthrough infections — where the infection takes place despite the completion of a full course of vaccination.

To make matters worse, many such cases are being reported among the frontline warriors, especially in healthcare settings.

Rising infections

India has been witnessing a sudden and sharp increase in the number of COVID-19 infections in recent weeks, starting in Maharashtra in March and subsequently spreading to other states including Delhi, Uttar Pradesh, Chattisgarh, Tamil Nadu, Karnataka and Kerala.

Take the case of Delhi, where daily case numbers have gone from less than 1,000 to nearly 23,000 in a matter of four weeks. Here, serosurveillance reports conducted before the latest surge had indicated the presence of SARS-CoV-2 antibodies in over half the population.

Therefore, the sudden surge of new infections points to a dreaded phenomenon — ‘immune escape’ — where a virus acquires sufficient mutations in its genome to escape detection by the antibodies generated by the human body during previous rounds of infection.

The case in favor of immune escape is based on two pieces of evidence: the rising number of reinfections among those who were supposed to be immune due to previous infections or vaccination, and early data pointing to the presence of a large number of mutant strains in states like Maharashtra and Kerala. Studies conducted in places like Delhi and Uttar Pradesh are unlikely to give a vastly different picture.

The government has tried to link the rise in cases to the relaxed attitude adopted by the citizens after case numbers started falling in late 2020.

Nevertheless, with more and more reports of breakthrough infections streaming in — particularly among healthcare staff — the union health ministry has initiated a programme to study cases of people testing positive for COVID-19 even after completing a full course of vaccination.

Mutation as the norm

Even as virologists are unsure whether to blame the rise in cases on new variants, they readily agree that mutations are the norm, and not the exception, as far as viruses are concerned.

Therefore, they point out, viral reinfections — even in fully vaccinated people — are not at all rare. However, given the pace at which infections spread during the second wave, such cases should be monitored closely and the contributing factors identified.

“Vaccine escapes can happen,” says Dr Vineeta Bal, M.D, former Staff Scientist, National Institute of Immunology, New Delhi, adding that the high number of COVID-19 infections during the first wave seems to have contributed to the emergence of a large number of virus variants.

“The speed with which this virus has infected so many people is partly responsible for the accumulation of virus variants and their spread. In most other epidemics or small outbreaks, this is likely to be less common.”

Critics say that had India conducted regular sequencing of viral samples, it would have caught the culprit variants early.

The authorities counter this by claiming that India has already sequenced more samples than many other countries ‘’but the missing piece is the link between these sequences and the epidemiology of the disease”.

Early leads

The health ministry said in April that the Indian SARS-CoV-2 Genomics Consortium (INSACOG) — a network of ten laboratories established in December 2020 for continuously monitoring the genomic changes of the SARS-CoV-2 virus in India — has so far genome sequenced more than 13,000 samples. INSACOG has shared the genome sequencing data with various states multiple times since March 26.

As of April 15, 2021, a total of 13,614 whole-genome sequencing WGS samples had been processed at the 10 designated INSACOG labs. Of these, 1,189 samples had tested positive for variants of concern for SARS COV-2 in India.

These include 1,109 samples with UK variants; 79 samples with South African variant and 1 sample with the Brazil variant.

Quoting INSACOG data, Kerala government said in April that 30% of the samples analyzed from the state comprised the highly contagious B.1.1.7 variant, commonly known as the UK strain, while 7% contained the so-called ‘double mutant’ — first reported by researchers in Maharashtra.

Even the South African variant, which is resistant to Covishield vaccine used in India, was also detected, albeit in only 2% of the cases.

Curiously, Government of India has resisted any suggestion that the new wave may be caused by mutant variants of SARS-CoV-2 — a stand that has not been challenged by the scientific community who lack ground-level data.

Given that there is practically no publicly available genome-level data on the situation in places like Delhi and Uttar Pradesh, most virologists and epidemiologists are currently unwilling to link the soaring numbers with the emergence of new variants of SARS-CoV-2.

Variants galore

Among these new variants, the British variant is believed to be about 60 percent more contagious and 67 percent deadlier than the original version of the virus.

Also called 20I/501Y.V1 or the B.1.1.7 lineage, the strain carries a mutation in the S protein (N501Y) that affects the receptor-binding domain (RBD).

Presently dominant in at least 10 countries, the B.1.1.7 variant is becoming the dominant strain in many parts of the world, spreading in at least 114 countries. It currently represents around 98% of new cases in Britain and up to 90% of new cases in some parts of Spain.

The spotlight in India, however, falls now on a newly discovered variant with two mutations that do not match previously catalogued variants of concern. This ‘double mutant’ has been found in 15–20% of samples from Maharashtra, India’s worst-hit state, reported INSACOG.

The variant carries two specific mutations of concern – E484Q and L452R – and virologists believe it is both more contagious and can cause re-infection.

This lineage is now spreading not just in Maharashtra but also in West Bengal, Kerala and several other states and even abroad. As many as 77 cases of this new variant first detected in India were found in the UK by mid-April.

The two mutations are likely to improve the virus’s binding capacity to the receptors and evade antibodies. There may be a separate lineage developing in India with the L452R and E484Q mutations coming together, say researchers.

Once the researchers upload their data to GISAID — a global science initiative and primary source for open access to genomic data of influenza and coronavirus — scientists from around the world will be able to determine whether the “double mutant” is the same lineage as the one found in the UK, or whether this combination of mutations emerged independently, as was the case for the K417N/T, E484K, and N501Y trifecta of mutations that came together in Brazil and South Africa to give rise to their strains, P.1 and B.1.351.

B.1.351 — also called the 501Y.V2 — is another mutant circulating India, throwing up a significant challenge to the currently available vaccines. First detected in South Africa, this variant has multiple mutations in the spike protein, including K417N, E484K, N501Y. Unlike the B.1.1.7 lineage detected in the UK, this variant does not contain the deletion at 69/70.

It has been found to reduce the effectiveness of some vaccines, including AstraZeneca’s, which is being widely used across India. Evidence also indicates that one of the spike protein mutations, E484K, may affect neutralisation by some polyclonal and monoclonal antibodies which are used against previously circulating variants.

South Africa’s second wave of coronavirus infections peaked in January 2021 was driven by this recently discovered variant.

The variant also was identified in Zambia in late December 2020, at which time it appeared to be the predominant variant in the country, according to the Centers for Disease Control and Prevention CDC, USA.

Finally, the P.1 variant or the Brazilian variant, which is behind a deadly COVID-19 surge in the Latin American country, is more contagious than the original form of the virus and also contains a mutation that scuppers the vaccines’ effectiveness.

This variant has 17 unique mutations, including three in the receptor-binding domain of the spike protein that has been previously linked to increased transmission and immune evasion.

A recent study reported on a cluster of cases in Manaus, the largest city in the Amazon region, in which the P.1 variant was identified in 42% of the specimens.

By modelling the spread of P.1 and its possible effects during Manaus’ second wave, the researchers estimated that the variant was 1.4–2.2 times more transmissible than other lineages and that it was able to evade some of the immunity conferred by previous infections. The findings have not yet been peer-reviewed.

Vaccines and variants

Low efficacy rates of vaccines can also lead to immune escape. However, experts rule out this possibility as all the major vaccines currently used in COVID-19 immunisation have generated enough data to support their efficacy against SARS-CoV-2.

Though developed at unprecedented speed, the debut mRNA vaccines have demonstrated an astonishingly high level of efficacy in large clinical trials.

Pfizer/BioNTech’s vaccine was 95% effective in preventing symptomatic disease found in clinical trials. The companies have said that real-life data in the US shows the vaccine is more than 91% effective against disease with any symptoms for six months.

Moderna’s vaccine was 94% effective in preventing symptomatic illness in trials, and 90% effective in real-life use. AstraZeneca vaccine was found to be 76% effective at preventing COVID-19 in key phase III clinical trial, the company announced on 25 March.

However, the key question is: Are these vaccines effective against the new variants?

The currently deployed vaccines tend to perform well against the B.1.1.7 or UK variant. Studies have found a slight drop in the numbers of neutralising antibodies responding to the B.1.1.7 virus after vaccination with Novavax and Moderna vaccines, but the protection these vaccines offer should still be sufficient to prevent severe disease.

This variant also had a negligible impact on the function of T-cells, which can kill virus-infected cells and help control the infection.

People given the AstraZeneca vaccine also experienced a mild reduction in the number of circulating antibodies when infected with the B.1.1.7 variant, preliminary data from a study suggest. But the effect was relatively modest, and the efficacy of the vaccine against this variant is similar to that of the original Wuhan strain of the virus.

This would indicate that the current crop of vaccines that are also based on early circulating viral lineages (including mRNA and inactivated vaccines) are also likely to be protective against B.1.1.7.

India’s Covaxin (BBV152) which contains a whole virion inactivated SARS-CoV-2 vaccine, induced antibodies that can neutralize the UK variant strains and other heterologous strains, a release from Bharat Biotech said.

Scientists, however, worry that the vaccines might be ineffective against SARS-CoV-2 variants with mutations in the spike-encoding gene. Most of the currently authorised vaccines are designed to trigger the production of antibodies targeting the SARS-CoV-2 protein called spike, which the virus uses to infect host cells.

In early 2021, researchers studying coronaviruses collected in California spotted a pair of SARS-CoV-2 variants that share several mutations affecting the spike protein.

The variants, B.1.427 and B.1.429, have been identified in 30 countries and most US states and, by February 2021, accounted for more than half of the SARS-CoV-2 viruses sequenced from California.

This is precisely the reason why the B.1.351 variant, which has four mutations in the spike protein, is found to be a potential challenge as it escapes most of the vaccines available today.

“The B.1351 variant has additional mutations of the RBD and NTD of the spike protein, which are targets of neutralising antibody, hence rendering it relatively resistant to antibody activity induced by past infection with ancestry virus as well as antibody induced by 1st generation COVID-19 vaccines that are mainly using the ancestry virus spike protein as the target,” says Prof Shabir A Madhi, Professor of Vaccinology at the University of the Witwatersrand, Johannesburg.

Johnson & Johnson’s single-shot vaccine’s efficacy rate plunged from 72 percent in the United States to 57 percent in South Africa, where the highly contagious B.1.351 variant is driving most cases.

The Sputnik V vaccine, developed by the Gamelaya National Centre for Epidemiology and Microbiology in Moscow was rendered mostly ineffective against the SA variant as the virus evaded antibodies elicited by the vaccine.

Experts say that the emergence of new variants might require the development of a new generation of vaccines.

Most of the vaccine makers are already working on booster shots for their vaccines to improve their effectiveness against the B.1.351 strain. Pfizer and Moderna are in advanced stages of development.

The only way to stop South Arica’s B.1.351 from gaining a foothold in other nations is to accelerate vaccinations.

In Europe, about a quarter of the population has received at least one dose of a vaccine by the end of April. These vaccines offer robust protection from B.1.1.7 and new cases across Europe have dipped slightly in recent days.

The EU countries began sequencing virus samples more aggressively in January and February.

All of the leading vaccines are expected to prevent serious disease and death from any of the variants, making any future wave in heavily vaccinated countries less deadly.

However, as an increasing proportion of the population is vaccinated, there is natural selection of mutations that allow immune evasion may occur. This will therefore require revaccination with antigens derived from the new lineages. Nevertheless, scientists continue to remain hopeful that vaccines will eventually defeat the variants.