Issue #86: Viruses, Vaccines and COVID-19: recruitment to the lymph nodes

Written by Nobel Laureate Professor Peter Doherty

As clinical investigators try to understand what’s happening in COVID-19 immunity, it’s easy to take a blood sample and analyse the various subsets of circulating lymphocytes but much harder to look closely at the events in the regional lymph nodes (LNs) where the virus-specific response develops (#85). Radiologists using imaging techniques can, of course, provide a lot of relevant information re LN size and so forth, but sampling the cell populations in the LN requires a needle biopsy.

Whole LNs can obviously be obtained at post mortem but, while such analysis (autopsies are increasingly rare in medicine) may give insights about the extent of damage in those who were fatally compromised, it does not inform us re what happens early in a normal, fit person. Much of our picture of the LN response following infection versus vaccination in COVID-19 is thus drawn from a long understanding of other diseases plus decades of experiments in species as diverse as non-human primates, sheep and laboratory mice (#41, #42).

Last week (#85), we got to the point of discussing how SARS-CoV-2 virus particles (virions) get to the regional lymph nodes, either in the lymph fluid (#9) or after being engulfed by monocyte/macrophages or ‘professional’ antigen presenting dendritic cells (APDCs). The vaccines we’ve been using in Australia all provide the genetic template (mRNA) for manufacturing the spike protein (#84), while infectious virus makes every structural or non-structural protein necessary to produce new virions (#85). Biopsy has demonstrated SARS-CoV-2 genome in the cervical LNs of, for instance a young, infected person who fully recovered, but we don’t know if much (or any) infectious virus is being made there in those developing effective immunity. Looking at post mortem material, monocytes and macrophages containing both viral protein and fully formed virions can be found in severely damaged lymph nodes and spleens from some of those who succumb to COVID-19. Is that damage caused principally by the virus, or by immune cells and other mechanisms that are trying to eliminate the SARS-CoV-2 infected cells?

When it comes to the SARS-CoV-2 mRNA vaccines, about 10 per cent of people experience some pain and swelling in the draining axillary lymph nodes (ALNs) after the first dose, while that goes up to 15 per cent or so after the second. That isn’t unusual for vaccines given into the arm. A review that pulled data together from a number of studies suggests that about 0.3 per cent of mRNA vaccine recipients can develop lymphadenopathy (severely swollen nodes that could be abnormal), as assessed by needle biopsy or imaging, which generally resolves in a week or two but can last up to six weeks. Many of those examined were cancer patients, in order to exclude the possibility of tumour metastases. Generally, the profile was one of ‘reactive lymphadenopathy’, perhaps a ‘super-enthusiastic’ immune response, in ALNs draining the arm where the vaccine was given.  

And, of course, with millions of vaccine doses being deployed some people, especially the very elderly with other disease problems, die within a month or so of vaccination. In a series of 22 such individuals (median age 85 years) receiving the Pfizer mRNA vaccine in North Germany, seven came to autopsy, with the conclusion being that there was no indication of allergic, inflammatory or other issues related to the vaccine. The status of the lymph nodes was not mentioned, which is generally an indication that anything observed was ‘unremarkable’.

The swelling of the regional ALNs in the armpit or the cervical LNs that drain the site of infection in the nose reflects that, triggered by the vaccine or the virus, locally-produced chemical mediators (interferons, lymphokines and chemokines), change the ‘molecular architecture’ of the small vessels in the LNs in ways that induce large numbers of circulating lymphocytes to leave the blood and ‘hang out’ there, at least for a while. This ‘recruitment’ process is part of a screening program to find those rare B cells and T cells with cell-surface receptors (BCRs and TCRs respectively) specific for SARS-CoV-2 antigens (#18, #19). The BCRs – the precursor forms of the immunoglobulin (Ig) molecules (#22) that will ultimately be secreted as antibodies primarily recognise ‘conformational sites’ (unique shapes) on folded proteins, with the SARS-CoV-2 spike RBD (receptor binding domain for ACE2) on free virions being the desired target (#20).

With the T cells, the TCRs are specific for SARS-CoV-2 peptides (short sequences from viral proteins) that bind into the tip of our own cell surface transplantation, or major histocompatibility complex (MHC) glycoproteins. That’s a complicated story (#29, #34) which, as we started it, led to my sharing a Nobel Prize with Rolf Zinkernagel (#32, #33). Basically different ‘sets’ of TCRs focus the CD4+ ‘helper’ cells and the CD8+ ‘killer’ cells onto the surface of viral peptide-modified APDCs so that these SARS-CoV-2-specific T lymphocyte populations can be selectively retained in the LNs. There, like the spike RBD -reactive B cells, they will start to divide and differentiate in the ‘nurturing environment’ of the LN ‘production facility’. That’s where we’ll go next week, to discuss the cellular immune response. To be continued