CME INDIA Presentation by Dr. S. K. Gupta, MD (Med), FICP, CFM (France) Clinical Asst. Professor GS Medical College, CCSU, Uttar Pradesh, India. Visiting Consultant, Max Super Specialty Hospital, New Delhi.
Today’s article is dedicated to the man with immense courage and patriotism – Neta Ji.
End of the Line?
Effective Vaccine and or Effective anti-viral Drug remain the keys to ending any pandemic. HIV was defeated using an effective antiviral. While Small pox was eradicated using a vaccine. Flu pandemic ended even without either of two. How will Covid End? Will the rich and mighty win this earlier? How will we come to know that virus is no more a threat?
Looking back at some of our previous pandemics or epidemics can give us an insight into some if these questions – both in epidemiological and social terms.
1918 Flu Pandemic
- Similar to COVID-19, the disease came in waves, making people feel as though they had defeated the virus, only to be struck with another round of illness. Around four waves occurred between 1918 and 1920, with the second wave of 1918 causing the majority of deaths.
- With no vaccine or treatments on the way, people attempted public health measures that are familiar to all: masking, discouraging public gatherings.
- So how did it end?
- The hypothesis is generally that the flu either could have become milder or ultimately affected enough people so that it no longer had populations to affect at such a scale that it could remain pandemic.
- Essentially, the virus either evolved to be milder or simply burned through the population.
- Ultimately, the virus ran out of people.
- And that meant there was a massive death toll before the virus dissipated. Flu affected more than 500 million people, and around 50 million people died worldwide. (Current Covid Pandemic Official toll is more than 5.6 million).
- 1918 flu may have ended through the virus becoming milder or herd immunity being achieved because so many people had been exposed; this is far from a guaranteed conclusion for COVID-19. Especially as we see continuing variants emerge and the possibility of infection evading the immunity conferred by vaccination.
- One could say that the pandemic ended not just when the third or fourth wave ended, but also there was a really active effort by the public and by politicians to forget it. There are countless memorials to those who died in the various Wars, there are no memorials to the millions of people who died during the pandemic, and it is not a coincidence.
If you want to understand the future – look at the history.
Smallpox
- Smallpox holds the unique distinction of being the only infectious disease that we have wholly eradicated through vaccination — a feat that was achieved nearly 200 years after a vaccine was invented.
So, can we vaccinate COVID-19 out of existence by effective vaccination?
- We could eradicate smallpox because it was a human-only virus, meaning that it could only spread between humans and didn’t have an animal vector, the way that many influenza viruses do. However, COVID-19 is thought to have originated in an animal before it made the jump to humans, and viruses with an animal vector always have the possibility of re-emerging as a novel human pathogen. And the sudden appearance of Omicron is making us rethink these lines.
- Those with smallpox also had distinct dermatological symptoms to identify them, which is not the case with most respiratory diseases.
- We’ve never eradicated a respiratory disease.
- Diseases don’t end because you have announced that you have an effective vaccine, which is something that we have learned the hard way through COVID-19.
HIV
- According to WHO, around 36.3 million people have died of HIV. The World could not end HIV; we just defeated it with effective drugs made available to the masses. The HIV epidemic taught the World that viruses don’t respect the man-made boundaries of land or money. Virus anywhere in the World is a threat to the whole of mankind.
- Widespread access to reliable treatments allows a person with HIV to live a whole life without fear of dying of AIDS or spreading the virus. These antiretroviral drugs work by stopping the virus from replicating inside the body. On similar lines, Pfizer’s new antiviral pill for treating COVID-19 is actually a protease inhibitor, a type of antiretroviral drug that was first developed to treat HIV.
Will Rich and Mighty end pandemic Earlier?
- Priority vaccination has already taught the World that one may not consider a pandemic to have “ended” when the threat has diminished within wealthier nations.
- We’ve seen that perspective rise in relationship to COVID-19, especially in the last few months, once vaccine access had largely been primarily achieved in wealthier nations, only to, over the last several weeks, recognize that without adequate vaccination around the World, we’re going to see, potentially, severe variants of concern continue to pop up around the World in places that lack adequate vaccination coverage.
- If COVID is raging in different parts of the World, it’s hard to really insulate oneself effectively. Just what’s happening with the Omicron is a classic example.
So finally, how would COVID-19 Go?
- There’s never a straightforward answer when we try to apply history’s pandemic lessons to a current or future virus.
- There’s rarely a peace agreement with a virus, like an end of a war.
- The pandemic end game is not just a matter of epidemiology or vaccine technology or science. It’s as much about politics and human behaviour.
- One of the most likely scenarios would be closer to the 1918 pandemic, with COVID-19 eventually becoming seasonal and milder.
- Much more like the flu, it’s going to be endemic, and then there’ll be particular seasons of the year where it’s more likely to be a potential outbreak.
- Pandemic seems to be driven by Governments – People just want freedom. Once the mortality comes less than 0.1% pandemic can be taken to have ended. However, no Govt is going to announce or televise that pandemic has ended. Slow withdrawal of restrictions allowing life to normal would be the only way to come to terms with tiny contagion rather than ceremonious celebration of triumph.
Why next variant has to be faster and sharper?
- Mutations in Virus
- It is the inherent property of Coronaviruses to change. The virus gets a chance to thrive and evolve when its stay in the host is longer. Hence immunocompromised hosts provide a perfect fertile environment for evolution by mutation. Many mutants evolve during the evolution process, but some mutations could be disadvantageous to the virus itself. Only the viruses with the evolutionary advantage will flourish in the host, slowly replacing the old virus or those with non-advantageous mutations.
- The thriving virus continues to make more copies and finally starts infecting a larger number of people in the society during sneezing and wheezing. If the new variant is much faster than the prevailing strain, it ultimately overtakes the previous mutant to become the dominant strain. Super-spreading events take to mutants to large numbers of people, wherein variants with entry advantage flourish and others fizzle out.
What is the supporting evidence to the theory of mutations occurring in Immunocompromised Host?
- Mutations found in variants of concern were spotted in SARS-CoV-2 samples isolated from people with compromised immune systems whose infections lasted for months. It led researchers to speculate that long-term infections might allow the virus to explore different combinations of mutations. Opportunities of mutation would obviously be limited in immune-competent hosts clearing the virus in a short time.
How have the Early Predictions about Sars Cov 2 fared with time?
- As the pandemic started in early 2020, many evolutionary biologists were quick to predict that the new pathogen would never be eradicated. Instead, it would become endemic. It would become the fifth coronavirus to permanently establish itself in humans, alongside four ‘seasonal’ coronaviruses that cause relatively mild colds and have been circulating in humans for decades or more.
What formed the basis of early predictions?
- Early lab experiments on stacked blood samples from 1980 to 2000 proved that people had immunity to coronaviruses from the recent past, but not to those from the future, suggesting that the coronaviruses have been evolving to evade immunity. And the recent lineages of Alpha, Beta, Gamma, Delta, and Omicron have proved the point.
Is SARS CoV-2 a fast-mutating Virus?
- No, genome sequencing early in the pandemic showed the virus has been picking up about two single-letter mutations per month. This rate of change is about half that of influenza and one-quarter that of HIV, both RNA Viruses. Slow change is curtsey, error-correcting enzyme coronaviruses possess rare among other RNA viruses.
How do scientists recognise significant mutations in SARS CoV-2?
- Though mutations can occur anywhere in the genome sequence of the virus, changes in the genes numbers from ~315 to ~525, which code for Receptor Binding Domain (RBD) of Spike protein, may confer attachment advantage to the virus. Similarly, the changes in genes coding for furin cleavage site (genes ~684 to ~687) might ease the entry of the virus into the host cell. All the variants of concern Alpha, Beta, Gamma, Delta, and Omicron have a primary mutation in the genes coding for RBD.
Evolution of Sars Cov-2 so far!
- An early mutation called D614G within the gene encoding the virus’s spike protein —seemed to offer a slight transmissibility boost. But this gain was nothing like the leaps in transmissibility observed with Delta and Alpha.
- Alpha variant spread at least 50% faster than earlier circulating lineages in November 2020. Around the same time, virologists in South Africa found another mutation-laden variant B.1.351 — later named Beta. A highly transmissible variant called Gamma was tracked to Brazil shortly after.
- Variants such as Omicron and Delta carry mutations that blunt the potency of antibodies raised against past versions of SARS-CoV-2.
- Whatever their origins, all three variants seemed to be more infectious than the strains they displaced. But Beta and Gamma also contained mutations that blunted the potency of infection-blocking ‘neutralizing’ antibodies triggered by previous infection or vaccination. It raised the possibility that the virus was beginning to behave in the ways predicted by evolution scientists like Jesse Bloom.
The Descent of Delta
- The Delta variant was identified in India’s Maharashtra state during a ferocious Second wave of COVID-19 in 2021. It was about 60% more transmissible than Alpha, making it several times as infectious as the first circulating strains of SARS-CoV-2. Delta behaved a kind of Super-Alpha and soon became the dominant variant driving a fresh surge of cases worldwide.
- Compared with other variants, including Alpha, Delta multiplies faster and to higher levels in the airways of infected individuals, potentially outpacing initial immune responses against the virus.
Origin of Omicron
- Most researchers expected the next variant to descend from Delta lineages. But Omicron undermined all those predictions. Instead, it turned out to be kin of Beta from Botswana. The variant harbours around 30 changes to spike, many shared with the other variants of concern.
- The swift rise in cases of Omicron in the world suggests that the new variant has a fitness advantage over Delta. Omicron carries some of the mutations associated with Delta’s sky-high infectivity. Early trends indicate that Omicron’ is 2-3 times more transmissible than Delta.
- Omicron’s rise is primarily due to its ability to infect people immune to Delta through vaccination or previous infection– the immune invasion effect inherited from its predecessor Beta. However, its limited ability to multiply in lung tissues, as proven by experiments in Hong Kong, is likely to make it a mild variant. However, its multifold replication capability in upper airways is the reason for its fast transmission, making it the dominant player in the third wave of the pandemic.
T cell advantage despite Omicron:
- Possibly repeated exposure to different versions of spike — through infection with different virus strains and/or vaccines — humans could finally build up a wall of immunity that SARS-CoV-2 finds difficult to invade. Possibly mutations could overcome some people’s antibody-related immunity but are unlikely to foil responses across an entire population, as T-cell-mediated immunity comes to rescue and seems to be more resilient to changes in the viral genome, maintaining protection against severe disease, hospitalization, and death. Patrolling T cells upon encountering the fresh challenge by the virus may take a week to ten days to mount an effective defence by forming a new crop of antibodies.
What could be Next variant like?
- The virus can go in multiple directions. The vaccines have acted as speed breakers as far as the severity of Covid-19 is concerned, but if they serve as permanent roadblocks, will depend upon waning immune responses and the evolution of the virus. It might be too early to comment upon either of the two.
- Nevertheless, the virus has been giving us nearly six months before descending into a new avatar. As the jabs are still highly effective, vaccinating as many as possible in the coming four to five months, especially in Africa and low-income countries, could stop the virus from unlocking changes that could drive a new wave. Just sending vaccines may not be sufficient as many poor countries lack the basic infrastructure like cold storage, transport, and workforce. With one and half months already gone, a quick and wholehearted concerted effort by wealthy and affluent nations can turn tides.
What makes Sars Cov-2 a perpetual virus?
- Vaccination may make the exiting population immune to the virus, but new children by birth will remain vulnerable to attack by an already established human reservoir of the virus, requiring regular childhood vaccination. Upcoming Nasal Vaccines by Bharat Biotech, AstraZeneca, and CanSino may help in not only blocking the chain of transmission but also dissipating the human reservoir.
- Also, being a zoonotic spill over virus, continued circulation in animal reservoirs, such as mink or white-tailed deer, brings some potential for surprising changes, such as immune escape or heightened severity. Hence, further research needs to be directed to define the animal source of the virus.
- Fatigue and Uncertainty driven by clueless political decisions may cost dear to the human race.
CME INDIA Tail Piece
Dr. Rajkamal Chaudhary, Asso. Prof of Med., Bhagalapur: Fourth wave and its going around…
I can think and Predict Fourth wave and even Fifth and Sixth wave of Corona virus to continue with the Pandemic to go on and on till 2025.
It is very simple to understand for the virus to change after a few months or years to change it self. Seeing its extinction, the virus uses its memory and changes itself to become weaker or Stronger virus.
I will now use my Polio Eradication Strategy where I worked for 16 years in India. The virus was the same as RNA Virus, where it changed between P123 to P1 and P3 later to Eradication of All in 16 years from India. The vaccine Strategy from Trivalent to Monovalent P1 was followed to Monovalent P3 vaccine and thus Elimination was followed, Similarly I expect the same in this virus, changing the Spike Protein numbers and the Genomic sequencing but the good luck we have the Vaccine is same. I don’t know for how much time this Strategy of Vaccine will run but it should not be like Polio Virus where the Strategy failed because of Resistance of Trivalent vaccine on Monovalent.
The Future will tell us about the Corona virus and we will be happy to know. This year is only 3 rd year going on we will have to know how we can survive with viruses.
References:
- Robertson D, Doshi P. The end of the pandemic will not be televised BMJ 2021; 375 :e068094 doi:10.1136/bmj-2021-068094
- Murray CJL, Piot P.The potential future of the covid-19 pandemic: will SARS-CoV-2 become a recurrent seasonal infection?JAMA2021;325:1249-50. . doi:10.1001/jama.2021.2828 pmid:33656519
- WHO Variant page: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/
- US CDC Variant page: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant.html
- US CDC Variant tracker: https://www.cdc.gov/coronavirus/2019-ncov/variants/index.html
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