15/08/2022

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As vaccination against COVID-19 is progressing at a steady speed in India, we are increasingly...

As vaccination against COVID-19 is progressing at a steady speed in India, we are increasingly hearing about western nations implementing a booster program. Doctors often get asked this question. Although we prefer to hear things in black and white as a yes or a no, the science of boosters is complicated. This article provides a plain English summary of the rapidly changing evidence to date.

However, it must be kept in mind that the ground we are standing on is moving as we speak, such is the speed of progression of not only the pandemic, but also medical research and publications. Therefore, the statements contained here are considered valid at the time of writing.

Sections:

  1. Basic immunology of vaccination

  2. What is the benefit of vaccination?

  3. What is meant by waning immunity?

  4. What is the current evidence on boosters?

  5. How can these be applied to India?

1.Basic immunology of vaccination

The above diagram explains the basic principles of COVID-19 vaccine immunology.


COVID-19 is a biphasic illness. The first phase is infection, which occurs in the nose and throat, and is primarily a mucosal disease. In many instances, this can occur without symptoms. To a large extent, this is prevented by vaccination. High levels of circulating neutralising antibodies in the initial months following vaccination reduces the chance of infection. This is depicted by the first fence or wall in the diagram above.

The second phase of the illness is organ damage, that is primarily immunologically mediated. This is believed to be from lack of prior exposure to the virus, when the adaptive immune response is delayed, allowing the virus to gain the upper hand.

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Vaccination ensures that the body is already familiar with the main components of the virus and elicits a timely adaptive immune response. This protects the internal organs in the event of a subsequent infection. This reduces the chance of severe disease by about 90%, compared to unvaccinated people without prior exposure to the virus.

The same principle applies to those who had prior infection by the virus. It is proven that at least a single dose of vaccine given subsequently will greatly enhance their immune response, a process called hybrid immunity.

The basic immunological principle of anamnestic response applies here. The initial encounter, either to natural infection or first dose of vaccine, generates an army of memory cells. They launch an extraordinarily powerful immune response when the second encounter occurs with the same antigen. Most present-day vaccines draw on this principle.

Although some western experts are now claiming that the mRNA vaccine was ‘always a three-dose vaccine’, most neutral academics agree at this time that the COVID-19 vaccine essentially is a two-dose vaccine, with the third dose being indicated only in selected instances. In fact, the new two-dose Hepatitis B vaccine works better than the older three-dose Hepatitis B vaccine. This shows that two doses are sufficient to generate an optimal immune response.

2. What is the benefit of vaccination?

Although they do protect against infection, protection from severe disease is the most consistent benefit from vaccination. In other words, a person who is vaccinated is about 90% less likely than an unvaccinated person to develop severe disease.

Breakthrough infection is the term used to describe an infection occurring in a fully vaccinated individual. The vast majority of these are asymptomatic or mild, with occasional severe disease occurring almost exclusively among people who are older.

Anecdotal data from India indicate that deaths following breakthrough infections (infection occurring after 2 dose vaccination) is extremely rare, and almost exclusively occurring in older individuals who have other illnesses. In fact, as vaccination coverage increases, the percentage of breakthrough infection also increases. This is because the pool of unvaccinated people shrinks to such an extent that the total number of infections from this subgroup is relatively small, although the chance of infection is higher.

Analysis of Kerala’s data from 13 November, for example, shows that unvaccinated people are ten times more likely to test positive, although 45% of all recorded infections occur among people who are fully vaccinated. This is because the denominator for the unvaccinated segment is small (4%) compared to the large denominator in the fully vaccinated segment (60%).

3. What happens after vaccination? What is meant by waning immunity?

Soon after the second dose, a maximum level of neutralising antibody is achieved. This remains high for approximately three months. During this period, the total number of infections is observed to be lower by 70-90%, in comparison to the unvaccinated group. This is called protection from infection.

However, in the subsequent months, as neutralising antibodies drop to a low baseline level, protection from infection also declines. This particularly happens when highly transmissible variants such as Delta arrive, and increased mingling occurs between people without masks in closed spaces. This is often collectively referred to as waning of immunity (see diagram above).

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Although this results in a greater total number of breakthrough infections compared to a few months earlier, most of them are mild and asymptomatic. There is no decline in the rate of progression of these infections to severe disease. The diagram under section 1 explains why this occurs.


At the same time, vaccinated people are over 90% less likely to develop severe disease or death, in comparison to unvaccinated people in similar age categories. Severe disease is caused by organ damage, and protection is mediated by a different arm of our immune system, which is T cells. This protection is expected to last many years. There is no indication at this point that this aspect of immunity is declining.

The most recent data from England, Sweden, Minnesota and Oregon are consistent with this observation.

However, a couple of caveats must be noted.

  1. The chance of progressing to severe disease is age dependent. This is called the exponential age gradient of COVID-19. For instance, an unvaccinated 75-year-old person is more than 100 times likely to progress to severe disease than an unvaccinated 20-year-old.

Following vaccination, there is an approximately equal reduction in risk in all the age groups, but the gradient remains.

In other words, a fully vaccinated 75-year-old is still more likely to progress to severe disease than a fully vaccinated 20-year-old. It is like saying, if a very thin person and an obese person both gain 20 kg, the obese person is still heavier than the other person.

  1. The number of severe disease cases that occur in the community is directly proportional to the number of infections that occur in the same community. In other words, if many people get infected, there will proportionately be a greater number of severe disease cases. 

Thus, even if the chance of progressing to severe disease is low, if a very large number of vaccinated people get infected, the total number of people who develop severe disease will also be larger. This applies even when the percentage protection remains steady over time. Basic principles of math state that a small percentage of a large number is still a large number.

What can be done to keep the pandemic under control?

The four fundamental measures of pandemic control are:

1) masks 2) avoiding indoor gatherings 3) improving room ventilation and air exchange rates 4) vaccination.

In other words, failure in any of these four arms will result in failure to control the total number of cases in a community. This, in turn, will increase the number of severe outcomes.

  1. What is the current evidence on boosters?

Early data about people who received a third dose of vaccine from England and Israel are now available. The above is a simplified graphical representation of the observations so far. This could change as more data becomes available in the future. 

Comparison of three groups of people, at 6 months past the initial two-dose vaccination. Booster data was observed in the immediate 1-2 months following administration of the 3rd dose. Long term data is awaited.


The Israel data show that there is a 5-fold reduction in the number of infections in the initial few weeks following the third dose. This is expected to occur as a result of an increase in the neutralising antibody levels. As the total number of infections are lower in the booster group, naturally the number of severe outcomes is also lower. 

The Israel data also showed that once symptomatic infection sets in, a person who received a third dose had the same risk of progressing to severe disease as a person who got two dose vaccination.

In Israel, the proportion of individuals that progressed to severe outcomes remained unchanged even after giving the third dose. While comparing the two dose and three dose groups, rates of progression of symptomatic infection to death were 1.31% and 1.36%, severe disease were 4.3% and 3.3%, and hospitalisation were 6.9% and 5.6% respectively. The absolute risk reduction (ARR) between the 2 and 3 dose groups was negligible at 0, 1% and 1.3% respectively for these three serious outcomes.

These numbers indicate that although the third dose predictably reduced the total number of infections, it did not provide any additional protection against severe disease among those who develop symptomatic infection. This immunological explanation of observation is provided in the diagram in section 1. In other words, the available published evidence on boosters points towards strengthening of the first wall of immunity, while no changes are made to the second wall. This is consistent with existing knowledge about T cell immunity. Further studies will bring clarity on this topic.

The UKHSA publication on 14 November showed a total reduction in the number of symptomatic infections in the boosted group, compared to the two-dose group. The authors comment that the duration of this protection remains unknown. If past experience with the vaccine is considered, neutralising antibody levels will likely start declining after the initial few months. Data about severe outcomes in England is awaited at the time of this writing. 

  1. How do these data apply to India?

Unlike the primary course of adult COVID-19 vaccination from almost a year ago, the decision about whether to take a booster is not a binary process. In other words, it is not a case of a clear yes or no for everyone; it has to be seen in the context of multiple factors. The current data on boosters is exclusively based on mRNA booster doses, and only short-term results are available. Emerging data will no doubt influence this decision.

Western nations that are giving third doses now are facing a COVID surge during winter months when they spend more time indoors; they are attempting to keep infection rates down to the extent possible. Providing boosters to those who are willing to take them is one such strategy. Also noteworthy is that in countries like the US, large sections of the population have refused vaccination. For instance, 38-47% adults of age 18-64 have not taken even a single dose of vaccine in the 10 states with lowest vaccine coverage, including Alabama, Louisiana and West Virginia. Adherence to other public health measures has not been optimal either.

Although these wealthy nations have a surplus stock, vaccine hesitancy and lack of public trust has caused the vaccination process to hit a glass ceiling. By contrast, 96% of adults in Kerala have received at least one dose of vaccine, indicating extremely low hesitancy levels.

On a related note, UK recently threw away 600,000 AstraZeneca vaccine doses that were past expiry date. Thus, the needs and priorities of various countries are different.

None of the vaccines that are being used in India have published data available after being used as a third dose among large numbers of people. This information is important not only because COVID-19 vaccines are a limited commodity for the world, but also because they are not completely benign products. Although the overall benefit for their use as primary course for adults far outweighs the risk, they do occasionally cause rare and serious complications including deaths – albeit in a tiny percentage of individuals. mRNA vaccines are known to rarely cause heart inflammation in younger individuals, the long-term outcomes of which are not known. Neurological complications and severe clotting disorders have also rarely been reported from the use of COVID-19 vaccines. The reported number of such complications is likely to be an underestimate because of scarcity of published data, and difficulty proving causality in many instances.

To put this information in context, most medical interventions have their share of complications, including for instance, Penicillin (an antibiotic) and Diclofenac (a pain-killer) injections which cause death in a tiny number of people who receive it. CT scans are rarely known to cause kidney failure. However, the larger benefit when these are used judiciously in the right setting is the factor that makes them worthwhile and life-saving to thousands of patients. It is prudent therefore to use the principle of minimum effective dose (i.e. no more than necessary) for these vaccines too, as is the case with all medications.

To give an example, if an elderly patient’s pain flare from an arthritic knee is adequately controlled on just one tablet per day of paracetamol, there is little role in adding more doses ‘just in case’. Other pain-relieving measures such as a bandage or warm compresses will reduce the need for medications. The fact that paracetamol is one of the safest medications does not mean it can be indiscriminately used. This is because even paracetamol can very rarely cause complications in some settings.

In the context of COVID-19, the risk and benefit vary enormously by different age groups, hence there cannot be a one-size-fits-all approach for vaccination, or for boosters. This is called risk-benefit analysis, which unfortunately is beyond the scope of this article.

Since there is a substantial age-related gradient in severe outcomes, individuals who are at greater risk of complications (either from age, comorbidity or from occupational increased risk of exposure to the virus) may be prioritised if and when booster doses are introduced in the country.

Those with immunosuppressive conditions must receive a 3rd dose. This is not because of waning immunity, but as their overall immune response to two doses might not be robust. 

Even after ten months of vaccine rollout, anecdotally there is no evidence that fully vaccinated individuals in India are developing COVID-19 complications at a greater rate than immediately following vaccination. However, it is important to carefully monitor for any change in the outcome patterns among vaccinated individuals. To India’s advantage is the fact that high levels of seroprevalence have been attained in several areas through natural infection, which is expected to reduce the impact of future waves.


This graph shows the stark difference in death risk by age group. Nearly all the COVID-19 deaths occur in those in the mid-40’s upwards. All of the younger age groups combined are represented in a tiny red bar to the right of the main bar in the graph. The same trend was observed in Kerala, where 97% of COVID-19 deaths occurred over the age of 40. This graph has important implications in prioritisation of vaccination, from the standpoint of death reduction. Courtesy Dr Duncan Roberson, UK. See original graph given separately above. Explanatory annotations by Dr Rajeev Jayadevan


From India’s public health perspective, it is important to complete the basic 2-dose vaccination process for the millions of adults who are yet to receive their first dose, particularly those who are over the age of 40. At this time, 1.14 billion doses have been administered in India. About 80% of the country’s adult population of 940 million has received at least one dose, while 40% has been fully vaccinated. The number of adults who are yet to receive vaccine in India is about 185 million. The best time to vaccinate will be the period in between waves, that is before the next surge occurs. When used judiciously in this manner, the available vaccine doses will translate into the largest reduction in deaths per dose used.

As discussed above, non-pharmaceutical interventions are effective at reducing the total number of infections, and, therefore, the total number of severe outcomes. Often, it is failure to adhere to these basic measures that result in a rise in the total number of cases. This fact has been repeatedly emphasized by experts, including the World Health Organization.

References

  1. SARS-CoV-2-specific memory B cells can persist in the elderly despite loss of neutralising 2 antibodies: Anna Jeffery-Smith https://doi.org/10.1101/2021.05.30.446322; BioRxIv May 31, 2021 15.

  2. COVID Mortality data from Oregon, US https://www.oregon.gov/oha/covid19/Documents/DataReports/Breakthrough-Case-Report.pdf

  3. US veterans COVID outcomes data from CDC

https://www.cdc.gov/mmwr/volumes/70/wr/mm7037e3.htm

4. Public health England mortality report

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1016312/Vaccine_surveillance_report_-_week_36.pdf

5. Mortality reduction from COVID-19 vaccination in South Africa

https://www.businesslive.co.za/bd/national/health/2021-09-09-covid-19-vaccines-offer-strong-protection-to-healthcare-workers-and-elderly-western-cape-data-show/

6. Audit of COVID-19 deaths by vaccination status, Ernakulam, India

https://www.thehindu.com/news/cities/Kochi/risk-of-death-lower-among-vaccinated-people/article36121132.ece

7. Comparative cost-effectiveness of a 2-dose versus 3-dose vaccine for hepatitis B prevention in selected adult populations, Hirst et al Vaccine Volume 39, Issue 33, 30 July 2021, Pages 4733-4741

8. Evidence that our immune system continues to improve over time.

https://www.biorxiv.org/content/10.1101/2021.05.07.443175v1

9. Improvements in immune repertoire occur in the months following vaccination

https://www.nejm.org/doi/full/10.1056/NEJMc2108829

10. No decline in vaccine protection against severe outcomes in Minnesota from May till October

https://twitter.com/RajeevJayadevan/status/1460246455516471302?s=20

11. Considerations in boosting COVID-19 vaccine immune responses, Philip R Krause et al. The Lancet: 13 September 2021

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(21)02046-8.pdf

12. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. Barda et al.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02249-2/fulltext

13. Guillain-Barré Syndrome following ChAdOx1-S/nCoV-19 Vaccine. Boby V. Maramattom. The Lancet September 13, 2021 https://www.thelancet.com/journals/lancet/article/PIIS0140- 6736(21)02046-8/fulltext https://onlinelibrary.wiley.com/doi/10.1002/ana.26143 16.

14. Parsonage-Turner Syndrome Following COVID-19 Vaccination: MR Neurography Sophie C. Queler Radiology https://doi.org/10.1148/radiol.2021211374 17.

15. Acute Transverse Myelitis (ATM): Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222) Gustavo C. Romain Front. Immunol, 26 April 2021 https://www.frontiersin.org/articles/10.3389/fimmu.2021.653786/full 18.

16. Symptomatic Acute Myocarditis in Seven Adolescents Following Pfizer-BioNTech COVID- 19 Vaccination, Mayme Marshall Pediatrics DOI: 10.1542/peds.2021-052478 https://pediatrics.aappublications.org/content/pediatrics/early/2021/06/04/peds.2021- 052478.full.pdf 19.

17. Effectiveness of Covid-19 Vaccination Against Risk of Symptomatic Infection, Hospitalization, and Death Up to 9 Months: A Swedish Total-Population Cohort Study, preprint at Lancet https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3949410

18. Analysis of Kerala Government Data on breakthrough infections

https://twitter.com/RajeevJayadevan/status/1459791712159633409?s=20

19. US vaccination tracker www.mayoclinic.org

20. UK threw away 600,000 AstraZeneca doses that were past expiry date

https://www.independent.co.uk/news/health/covid-vaccine-doses-astrazeneca-donations-uk-b1958000.html