Physical ‘strength’ of the multi‐protein chain connecting immune cells: Does the weakest link limit antibody affinity maturation?

Abstract

The affinities of antibodies (Abs) for their target antigens (Ags) gradually increase in vivo following an infection or vaccination, but reach saturation at values well below those realisable in vitro. This ‘affinity ceiling’ could in many cases restrict our ability to fight infections and compromise vaccines. What determines the affinity ceiling has been an unresolved question for decades. Here, we argue that it arises from the strength of the chain of protein complexes that is pulled by B cells during the process of Ag acquisition. The affinity ceiling is determined by the strength of the weakest link in the chain. We identify the weakest link and show that the resulting affinity ceiling can explain the Ab affinities realized in vivo, providing a conceptual understanding of Ab affinity maturation. We explore plausible evolutionary underpinnings of the affinity ceiling, examine supporting evidence and alternative hypotheses and discuss implications for vaccination strategies.

Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

“…We note that match-length is a proxy for affinity. To draw links between match-length and affinities measured using the equilibrium dissociation constant, K d , we recognize that affinity maturation typically commences with weakly binding antibodies, with K d ~10-100 µM, and can culminate with the strongest binding antibodies, with K d ~1-100 pM ( 30 ). In our simulations, these extremes span match-lengths 1 to 8, so that a gain of unit match-length would amount approximately to a 10-fold increase in binding affinity (or 10-fold lower K d ).…”

“…This process, termed affinity maturation, culminates, typically in weeks, in the selection of B cells with affinities that can be several orders of magnitude higher for the target antigen than those at the start of the GC reaction (26,27). What determines the final affinities is an important question in immunology and is yet to be resolved (28)(29)(30). Several studies have identified factors that influence affinity maturation (26,(31)(32)(33)(34)(35)(36)(37).…”

Low dose prime and delayed boost can improve COVID-19 vaccine efficacies by increasing B cell selection stringency in germinal centres

“…This process, termed affinity maturation, culminates, typically in weeks, in the selection of B cells with affinities that can be several orders of magnitude higher for the target antigen than those at the start of the GC reaction (26,27). What determines the final affinities is an important question in immunology and is yet to be resolved (28)(29)(30). Several studies have identified factors that influence affinity maturation (26,(31)(32)(33)(34)(35)(36)(37).…”