8 September 2021: Boosters, The Answer is 54

For those who read Douglas Adams’ “The Hitchhiker’s Guide to the Galaxy”, the number 42 has special significance.  Calculated over millions of years by the supercomputer Deep Thought, 42 is the “Answer to the Ultimate Question of Life, the Universe, and Everything.”

For boosters, that number is 54 international units (IU)/ml (with a 95% confidence interval of 30–96 IU/ml).

It would be unfair of me to stop the blog post without additional context, but 54 is as good of an answer to any question you might ask about the who, what, when, where, why and how of boosters.

So when we talk about booster shots, what is the core question we are asking?  At its essence, we want to know if  the vaccine series we received provides adequate protection from COVID-19. Fortunately Dr. David Khoury and colleagues from the Kirby Institute of New South Wales Australia have broken that seemingly simple question down into multiple parts, did all the complicated mathematics and provided us with an answer: 54.  So how did they arrive there (paper link at the end of the post)?

They start with what we know and, on most of this, we would all agree:

  1. Immunity to SARS-CoV-2 can occur either through natural infection (risky) or vaccination (less risky)
  2. Immunity has been shown to afford a degree of protection against reinfection and/or reduce the risk of clinically significant outcomes (i.e. severe disease, hospitalization, ICU admission, death)
  3. Natural/community infection have been estimated to have 89% protection from reinfection (100% in first 3 months) and vaccine efficacies range from 50 to 95% based on manufacturer
  4. The initial immune response to vaccination and/or natural infection inevitably wanes over time

So what do we not know?

  1. What is the duration of protective immunity from vaccination and/or natural infection?
  2. Do viral variants escape control from vaccine-induced and/or natural-infection immune responses?

Khoury and colleagues looked first at information on influenza protection where a hemagglutination inhibition (HAI) titer of 1:40 provides about 50% protection against the flu.  This level was established over many years using data from a standardized test and applied to serological samples from human challenge and population studies. Given the recency of COVID-19, there is little population data available and, certainly, there exists an ethical hurdle in deliberately exposing individuals to the virus.

However, there does exist information from vaccine studies as well as studies of patients who were infected and recovered from the virus.  While there exist a large number of differences in study methods, the authors investigated the relationship between antibody levels and viral protection. 

Despite the differences between study methods, comparison of antibody neutralization levels and vaccine efficacy showed a clear curvi-linear relationship between antibody levels and viral protection (Figure below)

To test their hypothesis, the authors looked at the Covaxin vaccine (developed in India by Bharat Biotech with the Indian Council of Medical Research) – their study results were published after the above analysis was completed.  Marked by the green dot in the Figure above, its efficacy sits right along the expected curve.

Based on these results, Khoury and colleagues then were able to estimate a 50% neutralization antibody equivalent across the studies coming up with a pooled estimate of approximately 54 international units (IU)/ml (95% CI 30–96 IU/ml).  This level varies by vaccine.  Among those commonly used in the United States, Pfizer had the lowest value at 19, followed by Moderna at 32 and then Johnson and Johnson at 105. Although this does not explain why Moderna appears to be more effective in the long haul as compared to Pfizer, it does show that the effective antibody level for the single dose J&J must be significantly higher to achieve meaningful protection.

In our office we have been running a semi-quantitative measure of the spike protein antibody among our patients for several months now. A positive response is defined as any value about 0.8 and the scale tops out at 2500 IU/ml.  Most of our patients cluster in the 300-800 range, with the caveat that most folks undergoing testing are over 65 years of age and had their vaccinations in January/February. Of interest, the highest levels we have seen are among those who had both natural infection and the vaccination.  I have only seen a handful of levels below 54, generally among those with known immunologic challenge due to medical condition or medication.

Now I’m not so naive as to believe that 54 is the answer, any more so that 8 months is the optimal time for a booster. But it does give us a starting point, and can better direct a national booster effort by effectively identifying those we should prioritize.

Khoury et al. Nature Medicine paper:  https://www.nature.com/articles/s41591-021-01377-8#MOESM1

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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