There is a lot to unpack regarding the situation (and outcome) of Djokovic vs the Australian government.  After reading a lot of ill-informed commentary, I thought I would offer a more scientific review of the ‘Djokovic defence’ – if you have been recently infected, does that give an exemption from being vaccinated?

Further, in business or social settings, should you now accept this ‘defence’ as a valid reason for exemption from vaccination practice?

Also, why might we need 4, 5 or more boosters?

We have learned that this ‘exemption’ was not the reason that Mr Djokovic was removed from Australia, but it poses significant questions that many workplaces and social groups will have to grapple with as people come back to work and may be excluded on the basis of their vaccination status.

Lets start with how it all works, why we get boosters and from there look at the evidence to support or deny the exemption opportunity.

Background: The immune response (1):

The immune system is broadly divided into the innate immune system and the adaptive immune system. Although these systems are linked in how they function, they each consist of different cell types with very different jobs.

The innate immune system comprises antibodies and immunoglobulins that are on hand to immediately deal with infective or invasive non-native cells and proteins.  They are the first line of defence and are fast acting.

The adaptive immune system is slower acting and is the control/moderator adaptive system of immunity.  The cells of this system act to produce specific antibodies to threats, create memories (for faster responses in future) and to do the ‘heavy lifting’ in neutralising and removing infections by viruses.  The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells. B cells produce antibodies.

Any virus that can cause disease in humans must have at least one immune evasion mechanism—at least one immune evasion ‘‘trick.’’ Without the ability to evade the immune system, a virus is usually harmless as it runs into the innate system that immediately responds and stops it infecting and replicating within the host. The innate immune system rapidly recognizes the infection and triggers the ‘‘alarm bells’’ of type I interferon expression and related molecules in the first few hours of infection. The innate immune response serves three main purposes: (1) restriction of viral replication within infected cells, (2) creation of an ‘antiviral state’ in the local tissue environment, including recruitment of other cells of the innate immune system, and (3) priming the adaptive immune response, which is a more complex and significantly slower process. The aim is to slow down the viral replication and spread and trigger the adaptive immune response.

Understanding immune evasion by a virus is important for understanding its pathogenesis and explains the roles and limitations of vaccines against them.  The avoidance of triggering the innate system by a COVID virus leads to its rapid infectiveness, its transmissibility (even after vaccination) and the lung-driven disease profile and fatality cascade of the virus.  In simple terms, the virus avoids primary immune defenders and rapidly spreads in the upper respiratory tract (URT) and lungs (less so Omicron variant).  This means cells in the airways are rapidly shedding virus (being a source of transmission) before the adaptive immune system can kick in.  The rapid impact in the lungs can lead to an over-response of cytokines and other defensive cells that work against the virus, but also critically impact lung function.  This leads to the need for ICU care and ventilation in some patients. It is therefore possible to explain the clinical profile of COVID-19 by understanding its powerful innate system evading mechanism.

Adaptive immune responses are slow due to the requirement of selecting and expanding virus-specific cells from the large pools of naive B cells and T cells.  The selected expansion cells need to be  specific for the detected viral structure. Adaptive immune responses can take 6–10 days after priming to control a viral infection due to the inherent time demands for extensive proliferation and differentiation of naive cells into effector cells that attack and remove the virus.

Once sufficient populations of effector T cells (helper T cells and cytotoxic T cells) and effector B cells (antibody secreting cells, known as plasmablasts and plasma cells) have proliferated and differentiated, they often work together to rapidly and specifically clear infected cells and circulating viral particles.

In COVID-19 infection, the virus is particularly effective at avoiding or delaying triggering intracellular innate immune responses associated with type I and type III Interferons in vitro and in humans. Without those responses, the virus initially replicates unabated and, equally importantly, the adaptive immune responses are not primed until the innate immune alarms occur. In an average case of COVID-19, that temporal delay in innate immune responses is enough to result in asymptomatic spread and onward infection. The presence of T cells and antibodies, once initiated, is associated with successful resolution of most cases of COVID-19.

Among COVID-19 cases, almost all individuals become seropositive, with almost all individuals become positive for SARSCoV-2 CD4+ T cells. This means that people who are infected create the T-cell repertoire of memory cells that allow the adaptive immune system to more rapidly and more accurately respond to further infection challenges. There are four major components of immunological memory to viruses: antibodies, memory B cells, memory CD4+ T cells, and memory CD8+ T cells. This seropositivity creates the basis for developed immunity either from infection or vaccination.

Vaccine immunity

Immune memory is the source of protection by almost all vaccines, and thus COVID-19 vaccine development is closely tied to the topic of immunological memory. An ideal COVID-19 vaccine would elicit long-lasting high levels of neutralizing antibody and would provide sterilising immunity to prevent disease and onward transmission. This would require a reservoir of the innate cells to be circulating to stop the ‘evasion trick’ and begin immediate viral clearance.

We are not seeing this at present, with vaccines more targeted at preventing serious COVID-19 disease. If the neutralizing antibody levels are sufficient to blunt the size of the viral assault, the presence of memory T cells may control the infection much faster and more effectively than a previously unexposed host. Priming of the immune system by a vaccine happens well in advance of virus exposure. Although lung infection is a major component of severe COVID-19 (and relatively slow), URT infection is important for transmission. Vaccines can prevent severe disease, or even most URT symptomatic diseases but do not prevent transmission of virus. At best the more rapid ‘primed’ response lessens the amount and timeframe of viral transmissibility. This is common in many vaccines, with the current pertussis vaccine preventing clinical disease but not infection, and probably not transmission as an example. As much SARS-CoV-2 transmission occurs early, during the pre-symptomatic phase, it is unlikely that vaccines in their current form are going to be able to reduce transmission greatly, but they will have a significant impact on speed of response of the immune system and therefore severity of disease. This speaks against the concept of ‘herd immunity’ as a way of stopping the spread of the disease.

Boosters

Boosters aim to reintroduce the ‘challenge’ proteins to the immune system, encouraging them to have greater expansion population of response cells ready to go.  If no re-exposure occurs, then the memory remains, but is ‘down-regulated’.  Re-exposure speeds up the response of the adaptive immune system offering enhanced protection from severe disease. It also ensures a certain population of innate cells that target the virus are still in circulation in a higher proportion.

Variants:

COVID-19 is a considered a relatively easy neutralization target (once it is revealed to the adaptive immune system). The infamous spike protein and its variants are easily neutralised in the vast majority of COVID-19 patients. It is therefore seen as unlikely that the virus will be able to evolve ‘escape variants’ that avoid the majority of immune memory generated in COVID-19 cases or COVID-19 vaccine recipients soon. Vaccines and infection should remain protective against future variants, however the concern would lie in variants that generate more severe disease earlier (before adaptive processes can be engaged).

For the Djokovic defence to be credible, proven infection of a person with COVID-19 (any variant) must create the expected adaptive immune response including formation of memory cells and reservoirs of expansion cells to protect the person from severe disease, and speed up the response to lessen the period of potential infectivity and transmissibility to others.

Impact of infection on immunity:

SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.

T cell activation, characterized by expression of CD38, was a hallmark of acute COVID-19. Similar findings have been reported previously in the absence of specificity data. Many of these T cells also expressed HLA-DR, Ki-67, and PD-1, indicating a combined activation/cycling phenotype, which correlated with early SARS-CoV-2-specific IgG levels and, to a lesser extent, plasma levels of various inflammatory markers. Many activated/cycling T cells in the acute phase were functionally replete and specific for SARS-CoV-2. Equivalent functional profiles have been observed early after immunisation with successful vaccines, showing that catching COVID has an equivalent cellular effect to being vaccinated. (2)

Virus-specific memory T cells have been shown to persist for many years after infection with SARS-CoV-1. In line with these observations, we found that SARS-CoV-2-specific T cells acquired an early differentiated memory phenotype in the convalescent phase, as reported previously in the context of other viral infections and successful vaccines. (2)

Many individuals with asymptomatic or mild COVID-19 (PCR positive) had highly durable and functionally replete memory T cell responses, often in the absence of detectable disease or immune system response, further suggests that natural exposure or infection could prevent recurrent episodes of severe COVID-19 in a similar way to vaccines. (2)

Scientifically, there is every reason to believe that the science behind the Djokovic defence would hold true.  This has been well supported by a number of biological, epidemiological, and clinical evidence (from reference 3):

Biological studies

  • Dan et al (2021): Approximately 95% of participants tested retained immune memory at about 6 months after having COVID-19; more than 90% of participants had CD4+ T-cell memory at 1 month and 6–8 months after having COVID-19 (4)
  • Wang et al (2021): participants with a previous SARS-CoV-2 infection with an ancestral variant produce antibodies that cross-neutralise emerging variants of concern with high potency (5)

Epidemiological studies

  • Hansen et al (2021): In a population-level observational study, people who had had COVID-19 previously were 80·5% protected against reinfection (6)
  • Pilz et al (2021): In a retrospective observational study using national Austrian SARS-CoV-2 infection data, people who had had COVID-19 previously were 91% protected against reinfection. (7)
  • Sheehan et al (2021): In a retrospective cohort study in the USA, people who had had COVID-19 previously were 81·8% protected against reinfection. (8)
  • Shrestha et al (2021): In a retrospective cohort study in the USA, people who had had COVID-19 previously were 100% protected against reinfection. (9)
  • Gazit et al (2021): In a retrospective observational study in Israel, SARS-CoV-2-naïve vaccinees had a 13 times increased risk for breakthrough infection with the Delta variant compared with those who had had COVID-19 previously; evidence of waning natural immunity was also shown. (10)
  • Kojima et al (2021): In a retrospective observational cohort of laboratory staff routinely screened for SARS-CoV-2, people who had had COVID-19 previously were 100% protected against reinfection. (11)

Clinical studies

  • Hall et al (2021): In a large, multicentre, prospective cohort study, previously having had COVID-19 was associated with an 84% decreased risk of infection. (12)
  • Letizia et al (2021): In a prospective cohort of US Marines, seropositive young adults were 82% protected against reinfection. (13)

Therefore, well conducted studies showing expected protective immunity after infection have been reported. In addition

  • Multiple epidemiological and clinical studies found that the risk of repeat COVID infection decreased by 80·5–100% among those who had had COVID-19 previously.
  • In a study of 9119 people with previous COVID-19 from Dec 1, 2019, to Nov 13, 2020, only 0·7% became reinfected.
  • Uninfected and unvaccinated people were infected at a rate of 4·3 per 100 people, whereas those who had previously been infected had a COVID-19 incidence rate of 0 per 100 people.
  • Frequency of hospitalisation due to a repeated infection was five per 14840 (0·03%) people and the frequency of death due to a repeated infection was one per 14840 (0·01%) people.
  • Robust immune responses and protection from severe disease remained intact to 10 months.
  • Risks relating to vaccination may increase in people who have previously been infected for a short period (undefined) after infection, but being infected is not a contraindication to vaccination.

In Switzerland, residents who can prove they have recovered from a SARS-CoV-2 infection through a positive PCR or other test in the past 12 months are considered equally protected as those who have been fully vaccinated (3).  However, in Australia, ATAGI (Australian Technical Advisory Group on Immunisation) advise that being infected is no contraindication to being vaccinated (13,16) and a delay of 6 moths of receiving a vaccination may be granted (16).  Mr Djokovic’s scenario hinges less on the ‘protection’ of infection as opposed to the issue of not being vaccinated as required by the definitions provided.

Vaccination versus Infection Issues:

As a person presents with ‘protection’ equivalent to vaccination (via natural infection and recovery), should this be seen as being ‘exempt’ in terms of workplace access?  One study suggests that individuals who refuse to get vaccinated and present at workplaces with infection ‘exemptions’ are less likely to follow other safety measures with relation to COVID (15).  The presumption is that the person feels that they have ‘beaten the system’ and as such become entitled to select which other rules may or may not apply to them.

Further, people who have had to exist under lockdown and restrictive conditions and which have submitted to vaccines often feel outrage that someone is afforded the same rights as them, even though they have ‘cheated’ the system (14).  This is a significant driver of backlash toward Mr Djokovic in the Australian community. This perceived lack of fairness can be a key lever in destroying positive workplace culture.

There are real medical reasons why some people may be at far greater risk when vaccinated, however this is a tiny fraction of the community.  Most Australians have had ample time to secure a vaccination if they intended to, or to seek appropriate medical exemption. The high rate of vaccination in Australia and the social constraints placed upon those who are unvaccinated is likely to suggest significant resistance to any future attempt to be vaccinated (and potentially follow other COVID-safe practices) in those who present such a Djokovic defence.

I can find no evidence relating to single infection versus multiple vaccination plus booster.  A single vaccination should provide equivalent protection to a single infection.  At present, the minimum standard for vaccination is being ‘double vaxxed’. With several key industries in Australia now mandating triple vaccination to be allowed to work. The aim appears (as outlined in the ‘booster’ section above) to maximise the potential speed of response of the adaptive immune system to any detected infection, thereby lessening the risk of severe disease and decreasing the transmissibility and total viral load.

Given the time schedule, a person using a single (recent) infection to provide a ‘Djokovic exemption’ is presenting the equivalent of a single vaccination.  Non-recent infections should be seen as invalid, with maximum time of protection being 10 months in studies and 6 months maximum delay time on getting vaccinated with medical exemption from ATAGI for more recent infections.

All communications regarding workplace access in Australia discuss ‘vaccination status’ rather than infection status.  The cases that have gone before the courts to be tested related to standing down workers based upon their lack of double (now triple) vaccination, rather than infection status.

Conclusion:

Individuals who are unvaccinated but can demonstrate a recent positive PCR and present a valid medical exemption for not receiving their vaccination could be granted a ‘vaccine exemption’ for a period of 6 months (16), however the positive result does not preclude them from getting vaccinated.  Although they should provide no additional risk to staff or customers – provided they engage in all other COVID safe behaviours (hygiene, social distancing, RAT testing, isolation practices, etc.) – other issues as to allowing the exemption in a workplace would need to be closely considered.

Understanding the science shows us why boosters are going to be an ongoing response to COVID, and why herd immunity is unlikely to be truly effective. Dealing with people who have a range of views on vaccination means understanding the science of COVID, vaccination strategies and legal frameworks in which they are applied.

Note: This is an example of a report sent to a large industrial organisation that was grappling with this question.  With everyone working in the business, the generation and presentation of this report helped senior management make effective decisions around their own risk and strategy re COVID and employee safety.  If you would like to discuss how a communication strategy or one off reports could be of value in your strategy and planning cycles, please get in touch now.

Key references

  1. Sette, A and Crotty, S (2021). Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 184, 4, P861-880, DOI:https://doi.org/10.1016/j.cell.2021.01.007
  2. Sekine et al., 2020, Cell 183, 158–168 DOI:https://doi.org/10.1016/j.cell.2020.08.017
  3. Noah Kojima, N. and Klausner, J.D. (2021) Protective immunity after recovery from SARS-CoV-2 infection. The Lancet,22, 1, P12-14, DOI:https://doi.org/10.1016/S1473-3099(21)00676-9
  4. Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 2021; 371: eabf4063.
  5. Wang L, Zhou T, Zhang Y, et al. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants. Science 2021; 373: eabh1766.
  6. Hansen CH, Michlmayr D, Gubbels SM, Mølbak K, Ethelberg S. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet 2021; 397: 1204–12.
  7. Pilz S, Chakeri A, Ioannidis JP, et al. SARS-CoV-2 re-infection risk in Austria. Eur J Clin Invest 2021; 51: e13520.
  8. Sheehan MM, Reddy AJ, Rothberg MB. Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study. Clin Infect Dis 2021; published online March 15. https://doi.org/10.1093/ cid/ciab234.
  9. Shrestha NK, Burke PC, Nowacki AS, Terpeluk P, Gordon SM. Necessity of COVID-19 vaccination in previously infected individuals. medRxiv 2021; published online June 19. https://doi.org/10.1101/2021.06.01.21258176 (preprint).
  10. Gazit S, Shlezinger R, Perez G, et al. Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections. medRxiv 2021; published online Aug 25. https://doi. org/10.1101/2021.08.24.21262415 (preprint).
  11. Kojima N, Roshani A, Brobeck M, Baca A, Klausner JD. Incidence of severe acute respiratory syndrome coronavirus-2 infection among previously infected or vaccinated employees. medRxiv 2021; published online July 8. https://doi.org/10.1101/2021.07.03.21259976 (preprint).
  12. Hall VJ, Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet 2021; 397: 1459–69.
  13. The Age, 15/1/22. P 4.
  14. Letizia AG, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study. Lancet Respir Med 2021; 9: 712–20
  15. Green R, Biddlestone M, Douglas KM. A call for caution regarding infection-acquired COVID-19 immunity: The potentially unintended effects of “immunity passports” and how to mitigate them. J Appl Soc Psychol. 2021;51:720–729. https://doi.org/10.1111/jasp.12779
  16. https://www.health.gov.au/sites/default/files/documents/2021/11/atagi-expanded-guidance-on-temporary-medical-exemptions-for-covid-19-vaccines.pdf

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