Long-term predictions of immunity after two doses of mRNA vaccine

The coronavirus disease 2019 (COVID-19) pandemic caused many countries to enact costly restrictions on freedom of movement and business. The rapid transmission of the disease and high mortality amongst at-risk groups such as the immunocompromised lead to the disease-causing over 4.9 million deaths and economic crises across the world.

Study: Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex. Image Credit: yudha satia/ Shutterstock

Mass vaccination schemes have begun to allow governments to begin to reduce restrictions. Still, fears are growing over variants of concern (VOCs) that are known to evade both vaccine-induced and natural immunity. The Delta variant now makes up 90% of new cases. As these VOCs spread and vaccination rates in the United Kingdom and the United States stall, a group of researchers from York University has investigated the long-term protection of two mRNA vaccines. Specifically, the researchers are looking at the Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273.

A preprint version of the group's study is available on the medRxiv* server while the article undergoes peer review.

The study

Traditionally vaccines are made from attenuated viruses. These viruses allow the immune system to recognize viral surface proteins and produce B cells and antibodies against them with no risk of infection. However, this is dangerous in some cases as inactivated viruses reactivate, or attenuated viruses gain traits from an active virus already within the body. mRNA viruses avoid this as they only use viral mRNA that encodes for a viral protein. The host's cell machinery is used to express this, producing the antibody target without any structural proteins or replicative ability. This completely removes the risks caused by more standard viruses.

mRNA  vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generally target either the complete spike protein or the receptor-binding domain (RBD) of the S1 subunit of the spike protein. The spike protein is critical for SARS-CoV-2 pathogenicity in humans. The RBD binds to angiotensin-converting enzyme 2 (ACE2) to permit viral cell entry, and the N-terminal domain of the S2 subunit is responsible for membrane fusion. Mutations that can create new VOCs tend to change the conformation of the monomers that make up the spike protein trimer. In wild-type, two or three monomers tend to stay in the 'down' conformation, which is better for preventing an immune response. In contrast, in variants, more monomers are likely to be in the 'up' conformation, which allows for better binding to ACE2 and more infectivity.

The researchers developed a novel in-host mathematical model that could describe the vaccination process when mRNA vaccines are administered. The model showed the time dependence of mRNA vaccine lipid nanoparticles, vaccinated cells, and the level of the immune response. The scientists used Monolix to fit clinical data to their model using non-linear mixed-effects models. IgG and IFN-y concentrations were log-transformed during fitting, as these can vary wildly over time. Final clinical data for two interleukins, IL-15 and IL-16, were gathered immediately after the second dose, so subsequent decay was not characterized.

The researchers found that the average rate of humoral degradation to be very similar with both vaccines, although the range could vary substantially. Unfortunately, due to the way IgG responses were entered into the model, the rates of decay for this molecule cannot be compared between the two vaccines. Different rates of immune response decay were predicted for different ages, with older individuals showing faster rates of plasma B cell death, which leads to higher immune response for younger vaccinated individuals over a longer period. This was most apparent when comparing 18-55-year-olds with over 70s.

Conclusion

The researchers highlight the importance of their work in helping to describe vaccine dynamics in mRNA vaccines. This information could be used better to inform vaccine manufacturers or public health policy workers, especially as infection rates rise again ahead of winter. This model allows clinically guided qualitative prediction for the loss of protection over time. This is supported by the model accurately predicting what observational studies have shown. For example, a study showed that the Pfizer/BioNTech vaccine will have dropped from 75% to 16% efficiency after seven months. This model shows IgG response also drops to 0.16 compared to peak rates following seven months. This could be an invaluable tool for helping to predict pandemic movements as vaccination rates slowly increase.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Sam Hancock

Sam completed his MSci in Genetics at the University of Nottingham in 2019, fuelled initially by an interest in genetic ageing. As part of his degree, he also investigated the role of rnh genes in originless replication in archaea.