Will the COVID-19 vaccines induce more robust immunity than infection with SARS-Cov-2 itself?

Respiratory viruses such as coronaviruses are notorious for evading the immune system^[1] and, in many recovered COVID patients, the level of antibodies (which neutralise the pathogen) are known to decline – particularly rapidly in those who only suffered mild disease^[2]. In contrast, vaccines are engineered to produce robust immunity without causing disease. This article considers whether the leading COVID-19 vaccines could cause robust immunity against subsequent infection with SARS-Cov-2, the pathogen that causes COVID-19, which has claimed 1.7 million lives globally at the time of writing^[3].

Immune evasion, or immune stimulation

Like all coronaviruses, SARS-Cov-2 is an “RNA virus”, meaning that its genetic code is stored on RNA (a similar molecule to the DNA that stores our own genetic code). Indeed, when our cells follow the normal process of executing their encoded genetic instructions, they produce “messenger RNA” (mRNA) molecules, which transfer the encoded information to the cell’s protein-manufacturing machinery. The virus hijacks this process by plugging its RNA into our protein-manufacturing machinery to make copies of the virus, which build up inside our cells to eventually burst out and infect yet more cells nearby.

Our cells have evolved ways of detecting such invasive – and potentially harmful – foreign RNA. One tell-tale sign is the presence of a “double-stranded” region, which is always produced when the viral RNA replicates. But viruses, in turn, have evolved ways to evade detection: For instance, they can sheath their replicating RNA within elaborate membrane structures called “replication organelles”^[1]. Additionally, the viral protein “papain-like protease” (PLpro), which our infected cells are forced to manufacture, directly interferes with certain immune signals that would otherwise alert the immune system to infection^[4]. The result is that our first line of antiviral defence is not triggered, so an appropriate immune response is not mounted initially and the infection gets out of control.

The COVID-19 vaccines produced by Pfizer and Moderna instruct our cells to make part of the virus surface protein – the “spike protein” – by delivering these instructions on mRNA. When the UK’s MHRA approved Pfizer’s vaccine, closely followed by the US FDA’s emergency use authorisations for both vaccines, they became the very first mRNA-based vaccines to be authorised for use in the population. As hoped, it seems that our cellular immune mechanisms are effectively triggered by the exposure to the mRNA in these vaccines: The immune system is effectively primed for subsequent encounters with the spike protein (and thus for the SARS-Cov-2 pathogen itself) and a high degree of protection against symptomatic COVID-19 is achieved.

The COVID-19 vaccine produced by AstraZeneca and the University of Oxford uses a different technology, which had been developed for vaccines against influenza^[5]. The technology uses an adenovirus, a type of DNA virus, as a “vector” to deliver a DNA molecule that encodes the SARS-Cov-2 spike protein. Adenoviruses are naturally immunogenic to humans. This led the developers choosing an adenovirus that normally infects chimpanzees, rather than humans: The high incidence of pre-existing immunity to natively human-infecting adenoviruses would lead to the vaccine being neutralised by the immune system before being able to produce the spike protein. (This vaccine-neutralising effect might lie behind an apparent reduction in efficacy, seen in clinical trials, when two full doses of the vaccine were administered, compared to a half-dose / full-dose regimen^[6].) Nevertheless, adenoviruses vectors induce potent cellular immunity to encoded recombinant antigens^[5], leading to long lasting immunity.

Therefore, the immunity achieved by vaccination should be durable. Although antibody levels may still decline substantially in under 6 months, it has been shown that white blood cells called “memory B cells” (which enable further rounds of antibody production) and “memory T cells” (which help orchestrate the immune response) are also produced by the mRNA and adenovirus vaccines^[7] – and these immune cells are thought to underpin enduring immunity. Therefore the immunity conferred by adenovirus based vaccines, and mRNA vaccines, should be considerably longer lasting than the impaired immunity induced by the coronavirus itself, although only time will tell for just how long.

New variants, moving targets

While a robust immune response should be achieved by the COVID-19 vaccines, what happens when the spike protein mutates, so that it no longer sufficiently resembles the spike protein delivered by the vaccine? The spread of a new variant, referred to as “VUI–202012/01”, which appears to be more infectious than previous strains^[8], led the UK Prime Minister Boris Johnson to ban millions of Brits from meeting their families for Christmas 2020, and led to dozens of countries refusing arrivals from the UK, in an attempt to curb its rapid spread. Reports focussed on a mutation of the spike protein at one particular point (“N501Y”), which is thought to enhance the infectivity of the virus. However, VUI–202012/01 is defined by 17 mutations overall^[9], including several more in the spike protein. It is therefore entirely possible that while the vaccines may confer robust immunity to the ‘old’ spike protein, they will not be so effective against the mutant strain: If the resultant antibodies and immune cells fail to recognise the mutant virus, it will evade the immune response. Thankfully, the new technologies such as the mRNA platform discussed above should be readily adaptable to new spike protein variants, meaning that updated vaccines could be produced without delay. Thus, the evolutionary battle between humans and virus will now proceed in the laboratory.

References

1. Kikkert et al, 2019. Innate Immune Evasion by Human Respiratory RNA Viruses: J. Innate Immunity 2020;12:4–20
2. Ibarrondo et al, 2020. Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19: N Engl J Med 2020; 383:1085-1087
3. Johns Hopkins online data resource centre.
4. McClain et al, 2020. SARS-CoV-2: the many pros of targeting PLpro: Sig Transduct Target Ther 5, 223 (2020)
5. Antrobus et al, 2014. Clinical Assessment of a Novel Recombinant Simian Adenovirus ChAdOx1 as a Vectored Vaccine Expressing Conserved Influenza A Antigens: Molecular Therapy, 22(3) 22, P668-674, MARCH 2014
6. Voysey et al, 2020. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK
7. Sewel et al, 2020. Covid-19 vaccines: delivering protective immunity: BMJ 2020;371:m4838
8. https://www.gov.uk/government/news/covid-19-sars-cov-2-information-about-the-new-virus-variant
9. Wise et al, 2020. Covid-19: New coronavirus variant is identified in UK: BMJ 2020;371:m4857