Public clonotypes and immune responses: we look at the research of Dr Elaine Chen at Vanderbilt University School of Medicine
Biotech writer Olivia Siviter recalls a presentation by Dr Elaine Chen, from Vanderbilt University School of Medicine at the Antibody Engineering & Therapeutics 2021 conference in Boston.
In this presentation, Dr Elaine Chen, from Vanderbilt University School of Medicine presents her research into the antibody responses of the SARS-CoV-2 Spike protein in convalescent and vaccinated individuals.
VDJ recombination describes the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation.
Diversity is achieved in VDJ recombination via combinational diversity, junctional diversity, somatic hypermutation and recombination of the light chains. This creates a highly diverse repertoire of antibodies/immunoglobins between individuals for the same disease.
When you compound this with the fact that different B cells are activated between individuals due to being exposed to different infections, it is unsurprising that B cells were thought to be individual to each person. However, Dr Chen’s research found 3 public clonotypes for SARS-CoV-2.
A public clonotype has been described as antibodies using the same heavy chain and light chain, V and J gene as well as the same CDR3 length with 70% clustered identity on the CDR3 chain. They are normally formed by convergent evolution.
The advantage of understanding public clonotypes of neutralizing antibodies is that functional and structural information could help inform rational vaccine design; if people make the same antibody response to the same disease it is implied that it is the most effective response to fight the disease. Public clonotypes may also create selective pressure on the epitope to inform population immunity.
In the SARS-CoV-2 pandemic, antibodies were being discovered at an unprecedented speed compared to other epidemics such as Ebola or Zika, making it a great opportunity to identify public clonotypes.
Before Dr Chen had started her research, most of the global research efforts had focused on the ACE2 receptor of the SARS-CoV-2 spike protein. Therefore, more was known about the S1 domain as it contained the RBD. More needed to be understood about the S2 domain to help identify any public clonotypes.
To do this, mABs that were reactive to the SARs-CoV-2 antigen were collected from 4 patients at the beginning of the pandemic (therefore they were unvaccinated individuals) and identified using antigen specific sorting techniques.
They were then tested for antigen reactivity and their functionalities were characterised. In total, 2085 mAbs were identified through these experiments and in other literature.
These mAbs had their sequences identified, and any clustered sequences present in 2 or more individuals were classified as public clonotypes. 11 public clonal types were identified, 3 of which were novel. The 3 novel clonotypes were named group 1, 2 and 3.
The reactivity of the clonotypes were tested against SARS 1, 2 and the RBD of SARS 2. Group 2 was found to be cross reactive to SARS 1 and 2 but did not target the RBD, which suggests that it may target the S2 domain as these are relatively well conserved between strains.
Further experiments confirmed that group 2 was reactive to the S2 domain making it the first public clonotype reactive to the S2 to be discovered.
Further experiments were conducted on the 3 groups to characterize their functionality. Notably, group 3 was found to have neutralization activity through ACE2 blocking by targeting the side of the RBD.
When converted to a germline revertant, group 3 still had some of its neutralizing properties. This suggests that it may have still had functionality before undergoing mutation, which could be the reason why these antibodies are found in multiple people.
The final part of Dr Chen’s research looked to understand if there were public clonotypes between vaccinated and convalescent donors.
This was done by taking samples from a vaccinated healthcare workers and comparing the antibody sequences with those of the convalescent individuals in the previous experiments.
They found a total of 37 public clonal types of which 26 were shared between vaccinated and convalescent donors. This may explain the high efficacy of mRNA vaccines as the body is creating a very similar immune response.
As a result of these findings, 4 classes of public clonotypes were proposed based off the variability of the epitope and the antibodies neutralizing potency.
Of the 4 classes identified, class 1, with high neutralizing ability for epitopes of low variability, is likely the most protective class in a population because they will bind to residues unlikely to be sustained with mutations due to loss of viral fitness.
Therefore, it is proposed that this class of antibodies should be used for rational vaccine design. Class 2 clonotypes, with high neutralising ability for epitopes of high variability will mirror escape variants.
This means that as the virus mutates, class 2 clonotypes will change as well, therefore they can potentially be used to help predict viral evolution.
The key conclusion drawn from these findings is that, by understanding different classes of clonotypes, we can predict antigen specificity from antibody sequence which can, in turn, aid rational vaccine design.
