New Research Reveals How Our Immune System Reacts to COVID-19 Variants

An important lesson for vaccine design.

Australian scientists investigating how our immune systems respond to COVID-19 have revealed that those infected by early variants in 2020 produced persistent antibodies, but these antibodies are not as effective against contemporary variants of the virus.

The study is one of the world’s most comprehensive studies of the immune response to COVID-19 infection. It suggests that vaccination is more effective than the body’s natural immune response after infection and demonstrates the need to invest in new vaccine designs to keep pace with emerging COVID variants.

The study, published July 6, 2021 in PLOS Medicine, was made possible through a collaboration between the University of Sydney, Kids Research, Sydney Children’s Hospitals Network, the Kirby Institute of UNSW Sydney, Australian Red Cross Lifeblood, St Vincent’s Hospital and NSW Health Pathology, as well as other local and international collaborators.

The team analyzed the serum of 233 individuals diagnosed with COVID-19 over 7 months and found that the level of immunity over time depends on the severity of the disease and the viral variant. They show that antibodies developed during the first wave were less effective against six variants, ranging from those seen in the second wave in Australia to three worrisome variants that triggered the global pandemic in the UK, Brazil and South Africa.

How do we study the immune response?

The serum from individuals infected with COVID-19 was interesting because it is the part of our blood that contains crucial information about our immune system. Analysis of the serum made it possible to create a detailed timeline of the level of ‘neutralizing antibodies’ produced against COVID-19 infection, and thus see if there was long-lasting immunity.

The study included a cohort of plasma donors. Credit: Australian Red Cross Lifeblood

Neutralizing antibodies are part of our immune system’s frontline arsenal that is activated during infection and vaccination. Their job is to protect cells that are commonly targeted by a pathogen (such as the SARS-CoV-2 virus that causes the disease COVID-19) from infection. The level of neutralizing antibody response can be a defining characteristic of how effectively our body fights disease.

Interestingly, a rare group of ‘superresponders’ was also identified as an exception.

This group of ‘superresponders’ had a stable and robust level of antibodies for all COVID-19 variants. The researchers say this group could be useful for exploring the potential of restorative plasma (using blood from recovered people to treat others) that has so far proven ineffective against severe COVID-19 disease. In addition, major donors can be closely monitored and their antibodies can be cloned for future therapeutic use.

Why is it important?

Co-senior author Associate Professor Fabienne Brilot of the University of Sydney and Kids Research, Sydney Children’s Hospitals Network, and her research team led the analysis arm of the study, using highly sensitive tools they developed to study the antibodies in detail.

Associate Professor Fabienne Brilot from the University of Sydney and Kids Research, Sydney Children’s Hospitals Network. Credit: Sydney Children’s Hospitals Network

“We can learn a lot from these people who were infected in the first wave in Australia, because they were infected with the same variant on which our current vaccines are based,” says associate professor Brilot.

“While the approved vaccines show good responses, our study highlights the importance of continued vaccine development, especially taking into account the differences in variants.”

Co-senior author Associate Professor Stuart Turville of the Kirby Institute said the study was conducted to examine the level, magnitude and longevity of immunity generated by COVID-19 infection and whether mutation of the virus increases immunity. endangers.

“What this work has shown us is that current observations on vaccines show that they offer a much broader protection against COVID-19 and its variants than the body’s natural immune response after infection, which is usually only protective against the variant of the virus that the person was infected with. We should therefore not rely on the body’s natural immune response to control this pandemic, but rather on the generally protective vaccines that are available.”

Key findings

SARS-CoV-2 antibody responses persist for up to seven months after infection. The immune response remained stable in some individuals and while it declined in others, no individual showed a negative response over the seven-month period. Levels of virus neutralizing antibodies were associated with the severity of COVID-19. Antibodies generated after early infection showed significantly reduced antibody binding and neutralization potential against globally emerging viral variants.

Methods:

The study analyzed the serum of 233 individuals diagnosed with COVID-19 from February to October 2020. There were two cohorts for the study: a hospital-based cohort of patients (the ADAPT study at St Vincent’s Hospital, Sydney) recruited during the first and second wave of infection in Australia and a national cohort of plasma donors (LIFEBLOOD).

10 COVID-19 strains and variants of concern/interest were examined, including:*

First known classified SARS-CoV-2 strain (Wuhan -1 D614) Alpha (B.1.1.7, United Kingdom) Beta (B.1.351, South Africa) Gamma (P1, Brazilian) Zeta (P2, Brazilian)

*Note naming conventions updated to reflect World Health Organization classifications

The researchers used a comprehensive set of tests that measured:

The lifespan and type of antibody response to Spike of different variants over time in serum of individuals diagnosed with COVID-19. Neutralization of infectious SARS-CoV-2 over time, by infecting cell lines that had surface ACE2 (which binds SARS-CoV-2 and targets the cell to initiate infection) with a particle designed to a version of the SARS-CoV-2 virus particle.

The study of many worldwide viral variants was made possible by the important collaboration between NSW Health Pathology and The Kirby Institute. The latter team developed cells to rapidly capture virus from smears obtained and rapidly sequenced by the Prince of Wales team led by Professor William Rawlinson.

Co-first author Fiona Tea. Credit: University of Sydney

Co-first author Fiona Tea who completed the research as part of her early postdoctoral fellowship at the University of Sydney and Kids Research at the Children’s Hospital in Westmead said: “What sets this study apart is the level and depth of analysis for neutralizing antibody levels in people recovering from COVID infection over time, including comparison of infections recovering from different viral variants.”

Reference: “SARS-CoV-2 neutralizing antibodies: longevity, breadth, and evasion by emerging viral variants” by Fiona Tea, Alberto Ospina Stella, Anupriya Aggarwal, David Ross Darley, Deepti Pilli, Daniele Vitale, Vera Merheb, Fiona XZ Lee, Philip Cunningham, Gregory J. Walker, Christina Fichter, David A. Brown, William D. Rawlinson, Sonia R. Isaacs, Vennila Mathivanan, Markus Hoffmann, Stefan Pöhlman, Ohan Mazigi, Daniel Christ, Rebecca J. Rockett, Vitali Sintchenko, Veronica C Hoad, David O. Irving, Gregory J. Dore, Iain B. Gosbell, Anthony D. Kelleher, Gail V. Matthews, Fabienne Brilot, and Stuart G. Turville, July 6, 2021, PLOS Medicine.
DOI: 10.1371/journal.pmed.1003656

This work was supported by Snow Medical and several grants, including two NSW Health COVID-19 Research Grants and multiple grants from the Australian Government’s Medical Research Future Fund (MRFF) among others. Please refer to the paper for full details. Associate Professor Brilot has received honoraria from Biogen Idec and Merck Serono as invited speakers. All other authors declare no competing interests. Ethical approval for this study was granted by St Vincent’s Hospital (2020/ETH00964) and Lifeblood (30042020) Research Ethics Committees.