BREAK COVID: COVID-19 breakthrough infections and correlates of protection

Vaccination against coronavirus disease-2019 (COVID-19) remains a key strategy
to control the COVID-19 pandemic. Waning protection and the emergence of
antigenically distinct variants with increased transmissibility increase the
likelihood of breakthrough infections with severe acute respiratory distress
syndrome coronavirus-2 (SARS-CoV-2). Breakthrough infections can be transmitted
and pose a risk for vulnerable subpopulations and long COVID. Recent data
demonstrate that even high levels of anti-Wuhan-Spike IgG have limited impact
on reducing the risk of breakthrough infection with viruses from Omicron
sub-lineages. The presence of other components of the immune response, such as
specific cellular subsets on the risk of breakthrough infections remains
understudied to date. Importantly, polyclonal T-cell responses do not seem to
be affected by mutations detected in the S protein, whereas these mutations do
lead to at least partial escape from neutralizing antibodies, making
standardised T-cell assessments even more important. National data,
incorporating national measurements, vaccine regimens, and vaccine take-up are
essential for data-guided vaccine policy making.

In this study, we aim to identify cellular and humoral immune correlates of
protection against breakthrough infections after either vaccination or natural
infection in representative subjects from the Dutch population. We want to
understand what the key immune markers are that determine the risk of a
breakthrough infection. In addition, the virus variant causing breakthrough
infections will be identified in order to answer the question: is it the bug or
is it the host. The top 3-5 markers with the strongest correlation will be
selected to be included in a risk-profiling algorithm. This algorithm can be
used by policy makers on a representative sample of the population for risk
stratification, optimalisation of the timing of vaccination and assigning
vaccines to the subgroups that will benefit most.

In this observational longitudinal cohort study, we will perform an in-depth
analysis of in total 48 cellular and humoral immune parameters in combination
with the SARS-CoV-2 variants involved in breakthrough infections. The study
will start using previously collected samples and will prospectively follow
participants for 9 months, monitoring for breakthrough infections. Risk at
breakthrough infections, and the levels of the 48 candidate markers for
protection will be compared in cases with breakthrough infections versus those
without a breakthrough infection. Novel virus variants identified from
nasal-throat samples will be sequenced and studied also in a humanized mouse
model.

The burden to participants consists of 3-5 routine venipunctures, one per
visit, and a mid-turbinate swab for combined throat and nasal sampling at
inclusion. Three visits will be scheduled about 3 months apart. In between
scheduled visits, participants are self-monitored for infections. They will be
asked to perform a standard COVID-19 home antigen test when displaying
COVID-19-associated symptoms. If the home test is positive, a mid-turbinate
swab will be taken by the subject at day 1, 5, and 14, and send to LUMC. About
2 weeks after infection a follow-up blood sample will be taken to determine
antibodies, T cell activity at Innatoss and biomarker-measurements at LUMC.
There is no immediate benefit for participants, besides contributing to a
better understanding of the immune response to SARS-CoV-2. The burden is
limited. Overall participation will take about 1 hour for 3 routine tests and 1
more hour in case of a breakthrough.