CME INDIA Presentation by Dr. Rajeev Jayadevan, MD DNB MRCP ABIM (Med/GE) Co-Chairman National IMA COVID Task Force.

The answer lies in knowing the different arms of our immune response.

  • The basics

Vaccines generate a two-pronged immune response, in very basic terms.
The first is antibodies, which are produced by B cells. 
The second is the T cell response.
These are “freshly made” by our body following encounter with the antigen – which is introduced at vaccination. Most vaccines introduce the spike protein, inactivated vaccines also introduce multiple other parts of the virus.
The “freshly made antibodies” will drop within about 3 months to a low base line – which is helpful in certain ways (antibodies not only neutralise virus, but have other immune functions too), but this low level will not be enough to prevent infection afterwards.
This is why people sometimes pick up infections even after receiving multiple booster doses.

It is not feasible to continuously give vaccine doses.

  • It is not feasible to continuously give vaccine doses with the hope to keep these antibody levels high. Imagine taking a vaccine shot every 4-6 months? Besides, there is concern that repeatedly doing these shots might diminish the quality of our immune response afterwards.
  • Antibodies are directed against large chunks of the virus protein and can easily be tricked by even a few changes within the protein. (E.g., Omicron’s mutations) These chunks are called epitopes. Some are large, some are small.

Imagine the epitope targeted by an antibody is a short story.

  • Just a few spelling mistakes change its whole meaning.
  • In other words, it is easy to alter the epitopes (antigenic targets located for example, on the virus spike protein) for antibodies, and the virus is constantly doing it as we speak.
  • In contrast, our T cells target much smaller epitopes located all over the virus, each of which are only 8 to 11 amino acids in length.
  • Besides, the epitopes of the same virus (or vaccine) selected by T cells can vary between individuals – this is based on our HLA “fingerprint. (In fact, HLA differences offers humans an evolutionary advantage, in that a single virus will not be able to wipe out the entire human race, see my prior tweets. This also explains why two people with the same baseline risk factors have different COVID outcomes sometimes)

Why is this important in our immune response?

  • To alter a T cell epitope is not easy, because there are about 3800 base pairs on the spike alone, and about 30,000 for the whole virus. Mutations are far too few to change ALL epitopes, as each one of them is so short.
  • It is like, if a book with ten chapters has a total of 30 spelling mistakes, how likely is it that a single sentence contains it?
  • Thus, among the approximately 15-20 T cell epitopes selected in each individual (they can also vary between people, as I mentioned above), it is almost impossible for the virus to alter each one of these epitopes, even with multiple mutations.
  • In other words, the second arm of our immune response still remains viable and able to counter infections, even by an altered form of this virus.
  • Note: T cells do not stop infection, because they can only work on viruses that have already entered the cells. Their job is to destroy – search, find and destroy virus-infected cells, each of which will otherwise release hundreds or thousands of virus copies.
  • By doing this, virus spread to other areas can be halted.

Why vaccinated people are less likely to die even if they got infected?

  • It is basically the job of antibodies to stop infection of the cells, but that’s not been a success as we know already in this virus’ case.
  • An easy way to remember this basic immunology is that antibodies are effective before the virus enters our cells, and T cells come to our rescue after the virus infects our cells.
  • (Antibodies cannot enter cells and kill viruses, therefore T cells arrive and destroy the whole cell, along with the budding baby virus particles inside it).
  • To simplify further, so far, the virus has been able to trick the first arm of our immune response (antibodies) – but NOT the second arm.
  • That’s also the reason why vaccinated people are less likely to die even if they got infected afterwards.

Quick Take Away

  • Someone who has received full dose of vaccine will have long-term memory generated in both T cell and B cell compartment.
  • They will rise to the occasion, if and when future infections occur.
  • Thus, it is not necessary to make a vaccine for every new variant.

CME INDIA Points to Ponder

Dr. Subir Roy, USA:

  • I agree on all points. Except on the point on why vaccinated people are less likely to die.
  • Death in COVID is not due to virus – but because of cytokine storm. Vaccination allows immune system to do two things:
  • Eliminate antigens in a targeted way.
  • Prevent immune system from overreacting to the target antigens.
  • The acquired “tolerance” prevents cytokine storm.
  • But the same mechanism is also responsible for VTE type side effects with Covid vaccines.

Dr. Murali Mohan, Pulmonologist, Bengaluru & Dr Sunil Nandwani, Jamshedpur: Superb.

Dr. Basab Ghosh, Agartala:

  • How much time is required for transcription of virus to newer strain and how fast scientists need to complete research to find new vaccine for each strain, then comes rapid manufacturing to cover huge population!!!

CME INDIA Tail Piece

  • The roadmap for COVID-19 vaccine prioritization has been updated by the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) to account for the effects of Omicron and the widespread immunity attained through vaccination and infection (28 March 2023 – News Release)
  • The revised roadmap by SAGE maintains the prioritization of protecting individuals who are at the highest risk of severe disease and death from SARS-CoV-2 infection, and also emphasizes the importance of maintaining strong health systems. In addition, the roadmap considers the cost-effectiveness of COVID-19 vaccination for low-risk groups, such as healthy children and adolescents, compared to other health interventions. The updated roadmap also includes recommendations on additional booster doses and the spacing of boosters, as well as taking into account the potential reduction of post-COVID conditions through vaccination, although the evidence on this is inconsistent.
  • According to Dr. Hanna Nohynek, the Chair of SAGE, the revised roadmap highlights the importance of vaccinating those who are still at risk of severe disease, including older adults and those with underlying conditions, and also encourages countries to consider their specific context in deciding whether to continue vaccinating low-risk groups while not compromising routine vaccines.
  • The roadmap outlines three priority-use groups based on the risk of severe disease and death, vaccine performance, cost-effectiveness, programmatic factors, and community acceptance. The high priority group includes older adults, younger adults with significant comorbidities, people with immunocompromising conditions, including children aged 6 months and older, pregnant persons, and frontline health workers
  • SAGE recommends an additional booster for the high priority group, which should be administered either 6 or 12 months after the last dose, depending on factors such as age and immunocompromising conditions. It is important to note that all COVID-19 vaccine recommendations are time-limited and apply to the current epidemiological scenario only. Therefore, the additional booster recommendations should not be interpreted as a suggestion for continued annual COVID-19 vaccine boosters. The aim is to assist countries in planning for the near-to-mid-term.
  • The medium priority group includes healthy adults typically under the age of 50-60 without comorbidities, as well as children and adolescents with comorbidities. SAGE recommends primary series and first booster doses for this group. Although additional boosters are safe for this group, SAGE does not routinely recommend them due to the relatively low public health returns.
  • The low priority group consists of healthy children and adolescents aged 6 months to 17 years. Primary and booster doses have been found to be safe and effective in this group. However, given the low disease burden in this group, SAGE encourages countries to base their decision on contextual factors such as disease burden, cost-effectiveness, and other health or programmatic priorities and opportunity costs.

Dr. S. K. Gupta, Consultant Physician Hospital, Delhi: In nutshell:

  • High Risk Groups – Elderly plus comorbidities: 2 + 2 Doses
  • Medium Risk Group – Healthy adults ~50: 2+1 dose
  • Low Risk Healthy – Less than 17 yrs.: No vaccine

References:

SAGE updates COVID-19 vaccination guidance (who.int)


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