Immune response – correlates of protection

Most likely over 95% of individuals infected with SARS-Cov-2 will recover, experiencing a spectrum of symptoms from negligible to severe.  Their recovery almost certainly relies on their immune system’s recognising and eradicating the virus and cells infected by it. A key factor in protecting us against many types of viruses is our generation of antibodies (a.k.a. immunoglobulins), that are produced by plasma cells of the B-lymphocyte lineage.  Usually, plasma cells developing high-affinity antiviral antibodies require help from virus antigen-specific CD4 T lymphocytes, while an additional mechanism of protection can be provided by virus antigen-specific CD8 T lymphocytes, which can directly destroy virus-infected cells. 

The development of virus-specific lymphocytes is known as an adaptive response, and usually takes at least a week to occur.  It depends on the prior activation of cells of the innate immune system, including dendritic cells and monocytes, that is driven in part by cytokines such as Type I Interferons.  Those interferons and other cells of the innate immune system, such as neutrophils, fulfil generic antiviral functions, keeping the virus at bay until the adaptive response takes over.  Other less well understood lymphocytes such as gamma delta T cells and Natural Killer cells are also strongly implicated in antiviral responses.

Although this collaboration of the innate and adaptive immune systems probably underpins our protection against essentially all pathogens, the details of it vary considerably. Indeed, the immune system is highly complex.  You can get some sense of this complexity by accessing the linked site,, that describes a large, Wellcome Trust-funded high throughput screen of genes affecting the immune system in mice. The data implicate hundreds of different genes as regulators of the immune system, acting on different cells in different settings. 

With so many mechanisms at its disposal, it is not surprising that the immune system deploys bespoke combinations of cells and molecules in response to different pathogens. For example, CD8 T cells or gamma delta T cells may in some instances play more important roles than antibodies. It is therefore important in every case to identify the precise correlates of protection (“CoP”):  those cells and molecules that collaborate to promote optimal defence against the pathogens.

Given its complexity it is no surprise that the immune system is different in each person, so when we get infected or vaccinated, we all start from different places.  You can get some sense of this by examining studies of immune responses to vaccination (Sobolev et al., Nature Immunology, 2016).  As a result of this variation, some people easily develop the appropriate CoPs whereas others struggle. Failure to reach the CoPs could result in failure to control the virus; and uncontrollable pathology.  This underlies the importance of identifying the CoPs in the case of SARS-CoV-2.

If we know the CoPs, we can understand why some get sick, and can design effective vaccines that drive the immune system along exactly the right pathways to reach those CoPs. However, there is another type of CoP that’s important – ‘correlates of pathology’. This reflects the fact that in some cases, the immune response seems to get out of control,  being too vigorous or progressing down an inappropriate pathway. This can cause damage to tissues, which in some cases reflects the over-activity of cytokines, such as tumour necrosis factor (TNF) or interleukin-6 (IL-6).  But again, the molecules responsible need to be identified because they can be different in different settings and different in different people even in the same setting.  Identifying these CoPs  offers ways to treat Covid-19 by neutralising their effects.