Immune responses to viruses
Viruses infect cells and take over the cell’s molecular machinery in order to replicate and spread. The immune response against viruses has two main components:
1. preventing cells becoming infected
2. recognition and destruction of virus-infected cells.
These two elements are carried out by different arms of the immune system. Antibodies are effective in limiting the spread of virus between cells in blood and body fluids. They can also prevent viruses from entering and infecting cells. Once a cell has become infected some of the cells of the immune system can recognise the infected cell and destroy it before viral replication is complete. The cells responsible for recognising and destroying infected cells are T-lymphocytes (T cells) and another type of lymphocyte, Natural Killer cells (NK cells). The relative importance of antibodies and lymphocytes in eliminating the virus depends on which virus is involved.
The basis of immunity to an infection is that the immune system specifically recognises an infectious agent that it has encountered and remembers it, so it can mount a faster and more effective response if it is encountered again. In the months immediately following a viral infection, assuming that the virus has been eliminated, antibodies against that virus will gradually decline. However, more important is that the numbers of cells that produce those antibodies (B cells) and the T cells that recognise virus-infected cells have increased enormously. Consequently, a subsequent encounter with the same infectious agent will be much more effective. It is important to understand that long-term immunity to infection is primarily dependent on this expanded population of long-lived ‘memory cells’, with a gradually declining contribution from antibodies during the first year.
In the case of COVID-19, antibodies against the external spike-protein appear to be most effective in preventing infection.The principle of vaccination is very simple – train the immune system to recognise and react against the infectious agent. Also, a vaccine should stimulate an effective immune response, while being harmless to the person who receives it. Since antibodies (produced by B cells) and T cells specifically recognise components of the virus a vaccine must include some of the virus components. Such a molecule recognised by a B cell or T cell is called an ‘antigen’. When they are activated by antigens in the vaccine, the populations of lymphocytes that recognise virus antigens are expanded and some develop into memory cells. Interestingly, but perhaps unsurprisingly, B cells and T cells recognise antigens in different ways. Antibodies are usually most effective when they bind to the outside of a virus, since they prevent it from binding to and infecting a new cell. In the case of COVID-19, antibodies against the external spike-protein appear to be most effective in preventing infection. In contrast T cells potentially recognise internal or external components of the virus, as they interact with infected cells which have viral antigens presented on their surface.
Different types of vaccine
There are several different ways to produce a vaccine against a virus (Fig.1). Earlier vaccines, used the virus itself but chemically inactivated in such a way that it could not produce an infection. Another route was to develop a variant of the virus that could replicate, but which did not produce any symptoms or pathology in the recipient. The two main types of polio vaccine were derived by these two strategies – inactivation or attenuation.
More recently, vaccines have been developed against individual components of a virus, for example against purified spike-protein of COVID-19. One limitation here is knowing which component(s) of the virus are important for inducing immunity. Also, recall that the antigens which stimulate B cells and T cells are often different. Moreover an immune response to a single virus component is often less strong than the response to an inactivated or attenuated whole virus. For this reason, such antigens may be modified to make them more immunogenic, or to favour one type of immune response.
The latest vaccines are produced by genetic engineering. The idea here is to use the genetic material of the virus, to induce production of viral components which then stimulate the immune response. One strategy for COVID-19 is to take the gene that encodes the spike protein and insert it into a harmless virus. The virus has very limited capacity to replicate, but it still produces the COVID-19 spike-protein which induces specific antibody production. This approach is used by the Oxford/Astra-Zeneca and Russian Sputnik V vaccines. Finally there is one more approach which immunises recipients with the viral antigen gene(s). It relies on the recipient’s cells taking up the gene and expressing it, so that virus antigens (but not virus) are produced by the cells of the body. This approach is relatively new and it is used by the Pfizer/Biontech and Moderna vaccines against COVID-19.
Testing a vaccine
Vaccines undergo rigorous trials, similar to drugs, before they are released for general use.Vaccines undergo rigorous trials, similar to drugs, before they are released for general use. The exception to this rule is where an infection is very dangerous or uncontrolled and it is necessary to put a vaccine into the field as quickly as possible. This was seen with Ebola virus in helping control outbreaks of Ebola in the Democratic Republic of Congo and Zaire. Where mortality from a virus infection is high, there is more tolerance of adverse reactions against the vaccine, and the normal extended testing programs can be abbreviated.
A normal testing program is carried out in four phases. The first phase examines basic safety of the vaccine in healthy volunteers. The second phase expands the initial trial to a larger and more diverse group of individuals (older, younger, different ethnic groups, etc.) and the third phase determines whether the vaccine is effective in a large cohort (thousands of people). To determine if a vaccine is effective it has to protect people from the naturally occurring infection and if the prevalence of infection is low in the community, then it takes longer to see whether the vaccine is effective. Due to the urgency to develop vaccines against COVID-19, volunteers were recruited as quickly as possible and where possible phase 1-3 trials have been overlapped to reduce the time before results became available. Phase-4 trials look for any long-term effects of the treatment and extend of necessity over many years.
It is important to note that any particular vaccine may not be ‘best’ for all people. Take for example a live attenuated polio virus vaccine. It works well in most people and is very safe, but in individuals whose immune system is suppressed, they may not control the vaccine strain of virus so well. For these individuals an inactivated vaccine is better.
Why do some vaccines work better than others?
Some vaccines are astonishingly effective. The measles vaccine is 97% effective and has not required any substantial modification for many years. The effectiveness of flu vaccine is variable from year to year and new vaccines are developed annually; to date no effective vaccine for HIV has been developed. In these examples the key difference is the stability of the virus. Viruses can mutate to evade immune responses and HIV and flu are very good at changing their genetic make-up, so they are no longer recognised effectively by the immune system. We do know that COVID-19 is relatively stable, although many different strains have emerged already. In at least one case a variant has affected the rate at which the virus spreads – this does not necessarily affect severity of disease or whether a vaccine is effective. Viruses that can evade immune responses are at a selective advantage, but a virus cannot mutate indiscriminately – if the virus loses its ability to infect cells then it can no longer spread. Antibodies directed against critical areas of the virus that are required for its infectivity are therefore likely to be most effective against different strains.
Another consideration is the type of immune response that the infection or vaccine induces. In some cases, immunological memory lasts for very many years, in other cases only a few years. We are not yet sure how long natural or induced immunity to COVID-19 will last, but we can predict that it will depend on memory cells, not just on antibodies.
We can also consider how different types of vaccine may be more or less effective in producing long-lasting immunity. Inactivated and attenuated virus vaccines contain many viral proteins so they can induce a wide range of antibody and T cell responses. This may be important if a virus mutates one of its antigens to evade an immune response. In this case there may still be effective responses to other antigens or other parts of the mutated antigen. One advantage of the new mRNA vaccines is that they can, in theory, be modified relatively quickly; if a new strain of virus is detected the sequence can be determined quickly and the sequence of the mRNA in the vaccine changed accordingly. Hence each type of vaccine can have its own advantages.
People often ask ‘How can I boost my immune system?’. Provided one has a balanced diet with sufficient nutrients and vitamins, your immune system will look after itself and look after you. The effectiveness of different types of immune response varies depending on the genetic make-up of each individual, but there is not much you can do about that. As an immunologist, my view remains that the only reliable way of boosting an immune response is by vaccination, and hence the focus of this article.