Disclaimer: The issue of immunity in SARS-CoV-2 is not yet settled. I have deliberately avoided several technical details, so this may seem as if I am oversimplifying things. Similarly, there are several finer points that I have omitted from this article since their inclusion will make the article very technical. This topic is hotly contested by people of differing viewpoints. I have merely tried to accurately present the available evidence. This article should not be taken as indicating official policy and should not be the basis for decisions regarding vaccination against SARS-CoV-2. Please consult experts in your area and comply with regulations in force in your location. This article reflects my personal opinion based on my review of scientific literature. You are free to disagree and have a different opinion.

Although the World Health Organization (WHO) recommends vaccination even after SARS-CoV-2 infection, there are several instances of celebrities (and ordinary people) refusing to get vaccinated against COVID-19 because they have developed antibodies after natural COVID infection. Their contention is that following natural infection they are immune (protected) from SARS-CoV-2. In this article I will discuss immunity against COVID-19 based on available scientific evidence and examine if having antibodies indicates protection against COVID-19.

The primary question I will try to answer is, ‘Are antibodies enough?’. The secondary question for this discussion is, ‘Should people get vaccinated after natural infection?’.

Background information:

How immunity works(1)

The development of immunity involves both humoral and cellular immune responses. Innate immune responses mount a vigorous defence early on. Cellular immune responses begin later and are more long-lasting.

Following vaccination, both B-cells and T-cells are stimulated. While antibodies from B-cells prevent the virus from entering cells, T-cells kill infected cells to prevent virus replication.

Development of immunity in SARS-CoV-2 infection(2,3)

Panel a: Infection with SARS-CoV-2 leads to activation of innate immunity and dendritic cells, which will drive the induction of virus-specific T-cell and B-cell responses.

Panel b: A predicted time-course of adaptive immunity to SARS-CoV-2.

The major steps in viral lifecycle and development of immune response in SARS-CoV-2 are(3):

1. Attachment of the SARS-CoV-2 virion to the cell surface via interactions with the ACE2 cellular receptor.
2. Entry into the cell.
3. Membrane fusion and release of RNA into the cell.
4. RNA translation to produce viral proteins.
5. RNA genome is copied and attached to the nucleocapsid protein.
6. Assembly of daughter SARS-CoV-2 virions.
7. Recognition of the spike glycoprotein and nucleocapsid protein (structural proteins) by the B-cell receptor.
8. B-cell produces spike glycoprotein-binding antibodies and neutralising antibodies targeting the Receptor Binding Domain (RBD) region of the spike glycoprotein.
9. Viral uptake by Antigen Presenting Cells (APCs).
10. Presentation of antigens, including epitopes from structural and non-structural proteins to T-cells.
11. Activation of T-helper cells.
12. Activation of Cytotoxic T Lymphocytes (CTLs)
13. T-helper cells produce cytokines
14. Cytotoxic T Lymphocyte recognition and killing of infected cells.

Immune response in individuals with or without previous SARS-CoV-2 infection(4)

Neutralizing antibody titres after administration of a second dose of vaccine in previously uninfected persons are much lower than the titre after a single dose of vaccine in previously infected individuals (panel 1B). Caution: Small sample size.

Key Messages:

There is no accepted correlate of protection (CoP) for SARS-CoV-2 till date. That is, antibodies have not been accepted as indicative of protection from SARS-CoV-2 till date.(5)

It is not known if detection of anti-SARS-CoV-2 antibodies by commercial assays indicates protective immunity.(6)

There seem to be several factors that influence the development of antibodies(3):

• Older women (>40 years) might develop antibody responses more effectively than other groups.
• Older (60-85 years) and middle-aged (40-59 years) patients have been shown to develop significantly higher titres of SARS-CoV-2 neutralising antibodies than younger (15-39 years) patients.
• Sex-specific differences in innate, antibody, and T-cell responses to SARS-CoV-2 have also been described.

There are important differences in the acquired immunity after natural infection and following vaccination. Antibodies elicited by mRNA vaccine are more focused to the Receptor Binding Domain (RBD) compared to antibodies elicited by an infection, which more often targeted other portions of the spike protein. Vaccine-elicited antibodies targeted a broader range of places on the Receptor Binding Domain than those elicited by natural infection. Thus, natural immunity and vaccine-generated immunity will differ in how they recognize new viral variants. Antibodies acquired with the help of vaccine may be more likely to target new SARS-CoV-2 variants potently, even when the variants carry new mutations in the Receptor Binding Domain.(7) Unfortunately, there is no consensus on this, with scientists reporting differences in vaccine-induced antibody titres against virus variants.(8)

Nevertheless, those receiving vaccine after recovering from natural infection tend to have higher antibody levels than uninfected persons who are vaccinated.(4,9) The limited evidence available suggests that a single dose of vaccine may be sufficient to induce an effective response in previously infected individuals.(9) There is a known (small) risk of developing antibody-dependent enhancement (antibodies may worsen disease) with higher antibody levels corresponding to more severe disease.(10) In the context of vaccination, this means that those with existing antibodies may experience more side-effects following vaccination than naïve individuals.

One study has reported that neutralizing antibody levels induced by mRNA vaccines against SARS-CoV-2 variants were similar to, or higher than that derived from naturally infected individuals.(8) Moreover, the immune response from vaccination is more predictable than after natural infection. Based on current evidence, antibody responses after infection vary widely by individual. Besides, antibodies are only one element in the body’s immune response, and these typically decline in a few months after infection.(6,11) The real memory in our immune system resides in the B and T cells, not antibodies themselves.(11) In fact, T cells are considered more important than antibodies by many authors.(2,10–12) T-cell response has been considered a better marker of immunity than antibody responses after natural coronavirus infection and is associated with reduced disease.(10,13) Moreover, memory B-cells and T-cells may be maintained even if there are no measurable levels of serum antibodies.(2)

From the above the following emerge:

1. There is no accepted correlate of protection against SARS-CoV-2 till date. Antibody titres alone cannot be taken as correlates of protection because:
   • Antibody titres are influenced by several factors (age, sex, etc.)
   • There is no accepted antibody titre level that indicates immunity/protection
   • The role of memory cells (particularly T-cells) is considered more important
2. Previously infected individuals may benefit from a single dose of vaccine. The choice of vaccine must be made carefully to minimize potential side effects due to the (small) risk of antibody-dependent enhancement.

References:

1.          World Health Organization (WHO). Update on COVID-19 vaccines & immune response Current global situation [Internet]. 2020. Available from: https://www.who.int/publications/m/item/update-52-covid-19-vaccines-and-immune-response

2.          Cox RJ, Brokstad KA. Not just antibodies : B cells and T cells mediate immunity to COVID-19. Nat Rev Immunol [Internet]. 2020;20(October):581–2. Available from: http://dx.doi.org/10.1038/s41577-020-00436-4

3.          Poland GA, Ovsyannikova IG, Kennedy RB. SARS-CoV-2 immunity : review and applications to phase 3 vaccine candidates. Lancet [Internet]. 2020;396(10262):1595–606. Available from: http://dx.doi.org/10.1016/S0140-6736(20)32137-1

4.          Anichini G, Terrosi C, Gandolfo C, Savellini GG, Fabrizi S, Miceli GB, et al. SARS-CoV-2 Antibody Response in Persons with Past Natural Infection. NEJM. 2021;385(1).

5.          Earle KA, Ambrosino DM, Fiore-gartland A, Goldblatt D, Gilbert PB, Siber GR, et al. Evidence for antibody as a protective correlate for COVID-19 vaccines. Vaccine [Internet]. 2021;39(32):4423–8. Available from: https://www.sciencedirect.com/science/article/pii/S0264410X21006587?via%3Dihub

6.          Spellberg B, Nielsen TB, Casadevall A. Antibodies, Immunity, and COVID-19. JAMA Intern Med. 2021;181(4):460–3.

7.          Collins F. How Immunity Generated from COVID-19 Vaccines Differs from an Infection [Internet]. 2021. p. 1. Available from: https://directorsblog.nih.gov/2021/06/22/how-immunity-generated-from-covid-19-vaccines-differs-from-an-infection/

8.          Chen X, Chen Z, Azman AS, Sun R, Lu W, Zheng N, et al. Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 ( SARS-CoV-2 ) Variants Induced by Natural Infection or Vaccination : A Systematic Review and Pooled Analysis. Clin Infect Dis. 2021;2(Xx Xxxx):1–9.

9.          Gobbi F, Buonfrate D, Moro L, Rodari P, Piubelli C, Caldrer S, et al. Antibody Response to the BNT162b2 mRNA COVID-19 Vaccine in Subjects with Prior SARS-CoV-2 Infection. Viruses. 2021;13(422):1–10.

10.        Hellerstein M. What are the roles of antibodies versus a durable , high quality T-cell response in protective immunity against SARS-CoV-2 ? Vaccine X [Internet]. 2020;6(100076). Available from: https://doi.org/10.1016/j.jvacx.2020.100076

11.        Block J. Vaccinating people who have had covid-19 : why doesn ’ t natural immunity count in the US ? Br Med J. 2021;374(2101):1–5.

12.        Plüddemann A, Aronson JK. What is the role of T cells in COVID-19 infection? Why immunity is about more than antibodies [Internet]. 2020. Available from: https://www.cebm.net/covid-19/what-is-the-role-of-t-cells-in-covid-19-infection-why-immunity-is-about-more-than-antibodies/#:~:text=Like B cells%2C which produce,the host cell%27s biochemical machinery.

13.        Dan JM, Mateus J, Kato Y, Hastie KM, Yu ED, Faliti CE, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science (80- ). 2021;eabf4063(371):1–13.