Roles of Antibodies vs. T Cells in Protecting against COVID-19

 On 09/02/2021, Professor Akiko Iwasaki has shared her insights on answering the below question:^[4]

The roles of antibodies vs. T cells in controlling primary infection, reinfection, and vaccine-mediated protection?

Figure 1.  COVID-19 vaccines immune activation modes (Source: [5])

Summary of Professor Akiko Iwasaki's Comments

Q: If B cells are needed to control primary infection
A: 

• B cells are not necessary for controlling primary SARS-CoV-2 infection.  
• However, in mice that have neither T cells nor B cells, SARS-CoV-2 persisted with no sign of clearance. Thus, innate immunity is insufficient, and adaptive immunity is required to control primary infection.
• Which implies that defects in T and B cell immunity predispose people for chronic COVID infection

Q: If CD4 (helper) vs. CD8 (killer) T cells are required for clearance of primary SARS-CoV-2 infection

A: 

• Depletion of either CD4 or CD8 had moderate effects on loss of viral control. 
• However, depletion of both CD4 and CD8 T cells resulted enhanced viral replication.
• Note that Effector CD8+ T cells (cytotoxic T lymphocytes) and CD4+ T cells eradicate infected, virus-producing cells via direct killing or by secreting cytokines, such as interferon-g (IFN-γ), which enhances inflammatory functions that support viral clearance.

Q: What is the role of CD4 (helper) T cells in primary SARS-CoV-2 clearance? 

A: 

• The role of CD4 T cells is mainly to support antibody (Ab) production, because in the absence of B cells, CD4 depletion had little impact on viral control.

Q: Are T cells or Ab sufficient to control primary infection with SARS-CoV-2?

A: 

• Ab is better than T cells in controlling virus.

Q: If mRNA vax or natural SARS-CoV-2 infection establishes lung-resident CD8 T cells

A: 

• While both induced comparable circulating CD8 T cells, natural infection is much better than vax in establishing tissue-resident CD8 T cells

Q: How well does the mRNA vax or primary infection protect against VOC, and how much of that depends on CD8 T cells?

A:

• The mRNA vax or prior infection protected 100% of mice, even after CD8 T depletion at the time of challenge.
• Both mRNA vax mice and convalescent mice were completely protected from disease with original strain (WA1) and the B.1.351 virus. Even without CD8 T, all vax & convalescent mice eliminated infectious virus.
• By immunizing with varying doses of the mRNA vax, a strong correlation was found between anti-spike IgG levels, neutralizing Ab and protection against COVID-19 disease.

Figure 2. Antibody effector functions (Source: [10])

Conclusion

• While T cells were sufficient for the clearance of primary infection, they were not required for protection against reinfection or vaccine-mediated protection.^[1]
• In [1], they did not test the sufficiency of T cells in vaccine-mediated protection. 
• However, a very nice study by @Masopust_Vezys shows the promise of adding T cell antigens to vaccines:^[2]
• They show that vaccination with a human adenovirus type 5 vector expressing the SARS-CoV-2 nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and K18-hACE2 mice. 
• Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. 
• This study supports the rationale for including additional viral Ags in SARS-CoV-2 vaccines, even if they are not a target of neutralizing Abs, to broaden epitope coverage and immune effector mechanisms.
• In [1], they did not test the Delta variant, with its high viral load and transmission capacity, vaccines that induce mucosal immunity (TRM, IgA) may become important to better prevent infection and transmission.^[3]
• In [9], it points out that immunological protection is not provided by antibodies alone. Vaccines engage the immune system’s T-cells as well. 
• T-cells are lymphocytes that respond not just to finished proteins, as antibodies do; they also recognize protein fragments. 
• Alessandro Sette, an immunologist at the La Jolla Institute for Immunology and his colleagues have shown that T-cells preserve 93-97% of their targeting capacity when faced with a new variant.
• It [12], it shows that:
• Antibodies play an essential role in host defense against pathogens by recognizing microorganisms or infected cells. Although preventing pathogen entry is one potential mechanism of protection, antibodies can control and eradicate infections through a variety of other mechanisms (see Figure 2). 
• In addition to binding and directly neutralizing pathogens, antibodies drive the clearance of bacteria, viruses, fungi and parasites via their interaction with the innate and adaptive immune systems, leveraging a remarkable diversity of antimicrobial processes locked within our immune system. 

References

1. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2
2. Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity
3. In the immune arsenal, antibodies offer best long-term hope against COVID
4. Prof. Akiko Iwasaki on Twitter
5. COVID-19 vaccines: modes of immune activation and future challenges
6. Immune Responses Dictate COVID-19 outcome
7. How Vaccines Might Improve Long Covid?
8. Designing spatial and temporal control of vaccine responses (good)
9. The wonky-spiked variant Omicron looks ominous. How bad is it likely to be?
10. Lu, L., Suscovich, T., Fortune, S. et al. Beyond binding: antibody effector functions in infectious diseases. Nat Rev Immunol 18, 46–61 (2018).
11. The state of complement in COVID-19
• The complement system is an ancient, evolutionarily conserved and non- redundant component of immunity. It is classically viewed as a liver- derived and plasma- operative system constantly scanning the blood and interstitial fluids for invading pathogens and self- derived noxious antigens.