Guest Editorial

To Boost or Not to Boost? Indian Perspectives – COVID Vaccination

Dr. Muralidhar Ramachandra*

Consultant, Critical Care, Kauvery Hospital, Bangalore, India

*Correspondence: tr.muralidhar@yahoo.co.in

Introduction

COVID vaccination is the only protection against the ongoing pandemic. Rapid development of efficacious vaccines, and immunization of the general population is an ongoing success story and is an effective strategy for reducing both viral transmission and disease burden. Initial hesitancy in general population and care workers in enrolling for COVID vaccination programme was the biggest challenge. Gradually vaccination drive gathered pace, with the states organizing even special drives. It has been a welcome change.

In India, vaccination drive began in January 2021. The time-gap between the two doses for Covishield was initially 4-6 weeks but then it was changed to 6-8 weeks. Subsequently, it was stretched to 12-18 weeks in many countries when the second wave was at peak and supply of vaccine at its lowest. Production, supply and distribution improved remarkably in July and consequently, vaccination drive gathered pace. Presently India has vaccinated 66% of the target population for the first dose and 22% with both doses. In Karnataka, its 78% for the first dose and 30% with both doses. A total of 82.4 crore doses have been administrated across the country. As production and supply increases, it may be time to consider reducing the gap between the doses.

Once we achieve a satisfactory state of vaccination with both the doses, the next item on the agenda may be studies and discussion, and framing guidelines on booster dosing. Down the line, we may probably have to think of it but no strong argument and data for it right now exist in our country. Present understanding of the vaccine is that it could save more lives if used in previously unvaccinated populations than used as a booster in the fully vaccinated population. Exceptions are population at high risk, like the elderly, health care workers and immune- deficiency states. Once we reach adequate vaccination -coverage of the population, booster doses may play a role in reducing infection and death. The countries which have vaccinated most of their population are considering giving booster doses to those who have been fully vaccinated.

Germany and Israel have announced their plans for booster shot programmes and countries like UAE, China and Russia have already started administering extra doses. Currently USA and Israel are the only countries who have approved mRNA booster in people with compromised immunity.

Booster dosing is appealing, but it has to be evidence based; whether indicated, and benefits and risk for individual and society have to be ascertained by studies in our population where many individuals have not yet received their first dose.

Rationale for the booster 

  1. Waning effectiveness of antibodies
  2. Emerging variants
  3. Lax precautions

Even after 2 doses, breakthrough infections of COVID are being reported as mild and moderate diseases. Two doses have been preventing severe illness, hospitalization and death against delta variant. So reduced protection against mild and moderate disease remain a concern after 2 doses.

Is immunity from vaccine waning?

We typically look at antibody levels or titers for vaccine efficacy. They usually spike, along with a surge in short lived B-cells, and then fall. What we don’t know is whether the drop reflects a decline in protection against the virus. Memory B-cells and bone marrow plasma cells continue to churn out antibodies but at reduced levels for decades.

The challenge is to determine the level of specific neutralizing antibodies or other immune markers which are more closely associated with vaccine effectiveness. We are seeking what is known as a correlate of protection. Knowing this threshold would allow us to determine more precisely whether and when the booster is necessary in response to waning immunity, or to the emergence of new variants that evade antibodies.

Studies

(1). Thomas SJ, et al. Safety and efficacy of the BNT162b2 mRNA COVID -19 vaccine through 6 months. N Engl J Med. 2021.

Data beyond two months after vaccination was not available till now. This study with six months follows up shows that, despite a gradual decline in vaccine efficacy, it has a favourable safety profile and was highly efficacious in preventing COVID-19 despite the emergence of SARS COV 2 variants including the Beta-variant.

(2). A study conducted by Jayadeva Institute of Cardiac Vascular Sciences and Research has found that COVID-19 antibodies are intact in 99% of the cohort, six months after both doses of COVID. They checked IgG neutralizing antibody by Elisa on 250 health care staff including doctors. All received second dose of COVISHIELD in in February this year.

The same staff were tested for antibodies in April and 79% had shown a positive antibody response, while 21% showed a negative immune response. When the tests were repeated in September on the same cohort, a positive immune response was seen in 99% of them, highlighting the importance of delayed immune response. A reference cut off value of 30% was considered a positive immune response.

Do booster doses actually work?

Vaccination produces an initial surge in the number of immune cells churning out antibodies and other molecules which then slowly drop. This leaves behind a small pool of long-lasting memory B and T cells that recognize the antigen when confronted, mount an immune response and thus prevent future infections.

A booster dose has several effects on these cells 

  1. It causes antibody making B cells to multiply, elevating the levels of antibodies against the pathogen once more. In time, their numbers dwindle again, but the pool of memory B cells left behind will be larger than before, leading to a faster, stronger response to subsequent exposure.
  2. Booster also promote a process called affinity maturation in which engage those B cells that have been triggered by the vaccine and travel to the lymph nodes. There they gain mutations, making the antibodies they produce bind to pathogens more strongly, potentially enhancing their potency.

Limitation

Numbers of memory B cells and antibody levels will eventually plateau with repeated boosting (or reinfection) but it is unlikely that such levels have been reached in people who have had the recommended regime of COVID-19 vaccine or a previous infection.

Studies

In the few trials that have tested this efficacy, the 3rd dose of vaccines developed by Moderna, Pfizer-bioNTech, Oxford Astrazeneca and Sinovac prompted a spike in levels of infection blocking neutralizing antibodies when administrated several months after the second dose. An ongoing UK trial will test various options of booster dosing including using a vaccine different from the original inoculation. Preliminary studies of these mix and match strategies. suggest that they could lead to more robust immune response, characterized by the high levels of both antibodies and T cells which kill infected cells and support other antiviral responses.

Side effects

These trials also suggest that common vaccine related side effects such as headache and fever aren’t very different from those seen with earlier immunization.

Do emerging variants and typing vaccine matter?

The surge in cases caused by the Delta variant has caused some countries to look more closely at boosters. It is clear from the trial data that protection against severe disease remains high. Pfizer-bioNTech and Moderna reported efficacy >90% against severe COVID-19 after 6 months. Real world data from Israel, the UK and elsewhere suggest that vaccines are highly effective at keeping people out of hospital even when Delta variant is the cause.

Type of vaccine

Countries that have relied heavily on inactivated virus vaccines, which seen to be less effective at preventing symptomatic infections than viral vector and mRNA vaccines, have been among the first to deploy boosters. The UAE is giving people who received Sinopharm’s inactivated virus vaccine a booster with pfizer-bioNTech vaccine and China plans to use domestically produced mRNA and protein-based vaccine as boosters for its inactivated virus vaccine. There is anecdotal evidence of large outbreaks in some countries such as Seychelles and Chile that deployed both inactivated virus vaccine and other vaccine types.

STUDIES

1. Bar-On YM. Protection of BNT162b2 vaccine booster against COVID-19 in Israel. N Engl J Med. 2021

  1. Booster dose reduced the rate of both confirmed infection and severe COVID-19 illness in a large Israeli population who were 60 years of age or older.
  2. Booster dose increased antibody neutralization level by a factor of 10.
  3. After 12 days, severe COVID is 20 times less likely with booster, than with 2 doses alone.
  4. 11.3-fold reduction in COVID infection.

Our analysis

  1. Good study.
  2. Reason for the study is well defined.
  3. An analysis of the Israeli data with respect to the outbreak of the delta variant indicated a high degree of waning immunity.
  4. In an effort to address the challenge presented by the delta variant and to reduce the load on the health care system, booster was approved first for the high-risk population on July 12 2021 and then to persons who were 60 years of age or older on July 30 2021.
  5. Target population clearly and cleverly defined
  6. Vaccination program was very successful with 2 doses, and plan for booster made sense to the government.
  7. Study observation done on their population who had better understand of the issues
  8. Extrapolating to Indian population at present is a challenge.

Biases

  1. Boostered patients may have a different risk for COVID or behave differently.
  2. Insufficient evidence of waning immunity.
  3. Short term wouldn’t necessarily imply worthwhile long-term benefits.
  4.  Would the impact of a 2-weeks lock down give similar results as booster?
  5. Confounding, detection and behavioural bias

CDC has advised for booster:

  1. For tumours and blood cancer.
  2. Advanced or untreated HIV infection.
  3. Organ transplant.
  4. Patients who have received Stem cells transplant and immunosuppressive medications.

Timing of boosters

Are vaccinations given months ago still preventing infections?

In the absence of a reliable correlate of protection, researchers are looking for signs of waning immunity in real world data from countries that have advanced vaccinations programs.

The question to be answered: Are people who were vaccinated early on getting infected at higher rates than those who were vaccinated more recently?

Studies

Ministry of health in Israeli, a country that has one of the world’s highest vaccination rates, released raw data.

On vaccination and infections from December 2020 to July 2021:

The ministry estimated that vaccine protection against both infection and disease had dropped from above 90% in the early months of its programme to around 40% by last June, a decline that could be due to the effects of Delta variant.

Those vaccinated between January and February 2021 were 53% more likely to test positive  for SARC-COV 2 during those 4 months  compared with March and April vaccination. The differences were even starker among the earliest and latest vaccinated.

Modifications/innovations in booster doses?

The effectiveness of boosting against the main variants now circulating and against even newer variants could be greater and longer lived if booster vaccine antigen is designed to match the main circulating variants. There is an opportunity now to study variant -based booster before there is widespread need for them.

A similar strategy is being used for influenza vaccines for which each annual vaccine is based on the most current data about circulating strains, increasing the likelihood that the vaccine will remain effective even if there is further strain evolution.

Questions to be answered before boosting 

  1. Booster for healthy ones or Immunocompromised ??

At present studies on booster dose are on elderly high-risk patients and in immunocompromised individuals. The lack of evidence around booster also means there is no clear picture about who would benefit the most. A large proportion of organ transplant recipients on immunosuppressive drugs do not generate high levels of antibodies after 2 doses of COVID-19 vaccine. One study found that only about half of them produced detectable levels. There is evidence that a third dose can elevate those titres but for many people, they remain below levels seen in other vaccinated groups. Unfortunately, without a correlate of protection, it is not clear what level is adequate for transplant recipients or older people whose immune system tends to be less robust than younger ones, or how to achieve such a level. In these groups’ booster may not help.
Octave trial

The OCTAVE trial included people with rheumatoid arthritis, psoriatic arthritis and other rheumatic diseases, cancers, liver disease, end-stage kidney disease, and those who have had stem cell transplants. Compared with healthy people, 40% of OCTAVE’s immunocompromised participants had low concentrations of SARS-CoV-2 antibodies – and a further 11% had no detectable antibody response at all – after two vaccine doses. However, patients’ T-cell responses were equivalent to those seen in healthy volunteers, even in those whose B cells were depleted.

  1. Booster after entire population is fully vaccinated??

Fully vaccinated rich countries consume more doses while several poor countries remain unvaccinated. There will be alarming vaccine gap between high income and low-income countries.

On September 1st 2021, ECDC (European centre for disease control) issued a technical report on booster dose. It concluded that fully vaccinated individuals in the general population are in no urgent need of booster shot. The report recommends to vaccinate unvaccinated people.

High income and upper middle-income nations have received 80% or more doses of COVID-19 vaccines administered around the world. WHO has warned that 42 states in Africa are likely to miss the target of vaccinating the most vulnerable 10% of their population by end of September. Around 3% of Africans has been fully vaccinated compared with 52% of Americans.

FDA, on September 22nd 2021, authorized people over 65 who had received Pfizer-BioNTech COVID vaccine to get booster shot at least 6 months after their second injection. FDA also authorized booster for those at high risk of becoming severely ill with COVID-19, or develop serious complications from the disease due to frequent exposure to the virus at their jobs. FDA may be also allowed in certain population such as HCW, teachers and day care staff, grocery workers and those in homeless shelter or prisons.  Roughly 22 million Americans are at least 6 months post their second dose of Pfizer vaccine according to CDC. About half of them are 65 and older. Millions who have received the Moderna and Johnson and Johnson vaccine are still waiting to learn whether they too can get booster.

Side Effects:

Several people have stronger side effects after the booster shot as the body has now a stronger, faster and better equipped response.

SUMMARY:

  1. Potential benefits of booster doses are uncertain whereas leaving vast swathes of the world population unvaccinated is sure to lead to more infections and deaths and emergence of troublesome variants.
  2. There is no guarantee that any immunity confirmed by a booster dose will last longer than that offered by the previous doses.
  3. Booster dose should be based on scientific evidence generated locally.
  4. The study should include epidemiology of COVID infection in the country on durability of protection provided by current dosage regime of vaccine and occurrence of adverse events with booster.
  5.  The developing world needs to get a clear picture and who will benefit from the booster. This is the primary concern.
  6. Third-dose efficacy in patients with absent or low antibody responses needs to be ascertained.

In India following factors need to be considered while inquiring into the subject of the booster dose

  1. Local studies
  2. Heterogeneous populations
  3. Populations density issues
  4. Behavioral/Lax precautions
  5. Type of vaccine/cold chain/antibody titres
  6. First administer the two doses of vaccine for the majority of populations
  7. Selections of patients
  8. Political issue
  9. Diverse demographic profiles.
Dr.-Muralidhar-Ramachandra

Dr. Muralidhar Ramachandra

Consultant

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