Issue #38: Local versus systemic, vaccine versus virus

Setting it Straight - Issue #38

Written by Nobel Laureate Professor Peter Doherty

The distinctive pathogenesis of COVID-19 versus pandemic influenza (#37) reflects that (in humans at least) the growth of flu viruses is normally limited to the respiratory tract, while it is very clear that SARS-CoV-2 can cause viremia, with the virus being distributed via the blood to other organs. The difference is thus between a localised and a systemic (blood-borne) infection. In both cases we do, though, see systemic effects. This can reflect the release of cytokines and chemokines from cells like neutrophils, monocytes and macrophages (#7) as part of the innate immune response. While limiting the growth of the pathogen to some extent before the more specific ‘adaptive’ immune effectors (antibodies and T cells) become available, these ‘innate’ chemical defenders commonly spill-over into the blood where they can, for instance, influence brain function and promote excessive vascular leakage into the infected lung.

Innate defence mechanisms have no ‘memory’ in the specific immune sense and are potentially triggered in all the body’s microenvironments. But, in mammals, the adaptive responses that set naïve T and B lymphocytes down paths that lead to their clonal descendants becoming antibody secreting plasma cells (#19 #21), helper or killer T lymphocytes (#33 #3) - or memory cells in any of those distinct lineages - develop only in the specialised anatomical niches of the secondary lymphoid tissue, particularly the lymph nodes and spleen. Birds also have a spleen, but lack discrete lymph nodes and, instead, have organised lymphoid tissue in other organ sites.

The ‘bird equivalent’ in us is the MALT, the mucosal associated lymphoid tissue that is particularly prominent in the appendix and Peyer’s patches of the gut wall (GALT) and plays a major part in defending us against enteric pathogens. There’s also the BALT (bronchus associated LT) but, so far as this involves lung tissue directly, the extent is very limited as the delicate tissue architecture required for gas exchange with the atmosphere does not allow for large accumulations of immune/inflammatory cells. The nose has some NALT but, more important from the MALT perspective in the oropharyngeal region are the adenoids (high up, at the back of the nose) and the oral, palatinal, lingual anyou!d laryngeal tonsils that form a defensive lymphoid circle called Waldeyer’s ring.

The operation is still relatively commonplace, but those of us who were children in the pre-antibiotic era almost invariably experienced the surgical removal of inflamed adenoids and tonsils. The procedure was generally performed as a ‘package’ by GPs, not specialists, with the very sore throat consequence for young patients being compensated by a transient diet of lemonade and ice-cream; a luxury in the deprived 1940’s. Come to think of it, has anyone thought to ask if severe COVID-19 is more common in those who experienced early tonsillectomy/adenoidectomy?

Following infection of the nose and upper respiratory tract with an influenza virus or SARS-CoV-2, the first place that the immunologically naïve lymphocytes of the adaptive immune response are likely to encounter infectious virus, virus-infected cells or viral proteins (antigens) will likely be in the MALT of the adenoids and tonsils. We always swallow some mucus (#10), so the tonsils will likely be involved in respiratory infections. Lymph (#9) from the tonsils and adenoids then flows on via the lymphatics to the discrete retropharyngeal and cervical lymph nodes. For those who lost their adenoids and tonsils as kids, these lymph nodes will be much more in the front line. When it comes to the lung itself, lymph drains to small nodes at the bifurcation of the large bronchi (airway tubes), the tracheobronchial nodes and, ultimately, the mediastinal nodes located midline between the right and left of the chest cavities.

We are, of course, inferring what happens in secondary lymphoid tissue during SARS-CoV-2 infection from a very long history of post-mortem studies of humans who died from various respiratory pathogens, with that understanding being enhanced by the analysis of tissue biopsies from sick patients and by rapidly evolving, non-invasive imaging techniques. Much of our more detailed understanding of immunopathogenesis to date still comes, though, from kinetic experiments with species like mice and ferrets, where animals can be sampled sequentially and in-depth studies made of the early infectious process, including what’s happening in the lymph nodes, MALT and spleen. The respiratory infection pathway may also be mimicked to some extent in those given a live-attenuated (weakened) influenza vaccine as an intranasal spray. This type of vaccine was used for decades in the old USSR, and an equivalent product (made by the Medimmune company) is available in the US and Western Europe.

Chinese scientists have produced (among many other formulations) a whole virus, chemically-inactivated (equivalent to the Salk polio vaccine) COVID-19 vaccine, which has been given to substantial numbers of people in the Chinese Republic and is also being used in Indonesia. Otherwise, all the vaccines that are being trialled, and are now beginning to roll-out, in the Western world are only dosing people with the SARS-CoV-2 spike antigens, especially the RBD, the human ACE2 receptor binding domain (#19). That may be as a protein or as the encoding nucleic acids (mRNA, DNA #6, or incorporated in a replication defective adenovirus #4) made in an ultra-clean, certified, GMP (good manufacturing practice) production facility.

These vaccines are, in the main, being injected (#17) intramuscularly (IM) – anyone who has ever been vaccinated will have had that experience of being ‘stabbed’ with a hypodermic needle. Alternatively, though no such COVID-19 vaccines are yet close to being approved, some product may be administered intradermally (ID), into the skin. What links vaccines given via the IM or ID routes in the upper arm is that they go straight into the lymphatic drainage from that region, either as free ‘product’ or after being taken up by specialised antigen-presenting cells (APCs) called the dendritic cells. There they travel via the lymphatic flow to the complex of axillary lymph nodes in the arm pit. What happens after antigen/APC-containing lymph gets to the lymph nodes is where we’ll go next. The basic point is, though, that the initiation of any SARS-CoV-2 spike vaccine response will be localised to a very limited anatomical niche (microenvironment) as distinct from the much broader bodily ecosystem involvement (#37) of a virus infection, particularly when we also factor-in the viremia that occurs in COVID-19.