Biological challenges in developing coronavirus vaccines

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Understanding more about the biology of the new coronavirus is essential for the design of vaccines, but is only the beginning of a long process leading to an effective vaccine. A vaccine must stimulate the right parts of the immune system to be effective, and safety is paramount. Good animal models for vaccine development are not available for the new coronavirus.

What we know from other coronaviruses

For a virus to multiply, it first needs to break into human body cells. The SARS coronavirus, which caused an outbreak of disease in 2003, does this by hijacking docking bays (receptors) on the outside of lung and gut cells. These receptors are normally used by an enzyme called ACE2 (angiotensin-converting enzyme 2) which helps regulate blood flow through vessels. The new coronavirus (SARS-CoV-2) uses the same receptor but binds to it with even greater strength. It does this using one of its four main structural proteins, the spike or ‘S’ protein which sticks out all over its surface.

How does the immune system deal with viruses?

Recovery from virus infections happens as a result of the activation of the immune system of the body, a system of proteins and cells that are distributed throughout the body, able to respond to invasion by viruses and other microbes. These proteins include antibodies, which lock on to bits of the virus such as the ‘S’ protein.

When the immune system is exposed to a virus, it responds by the selection and rapid increase of cells that produce highly specific antibodies that bind with great strength to viral proteins. These antibodies inactivate viral proteins that the virus needs to infect cells. They also help clear the virus from the body. A second part of the immune response is the stimulation of lymphocytes, a type of white blood cell. These lymphocytes help to produce antibodies. Some also can recognise and kill – ‘neutralise’ – the cells that are infected with virus.

Once someone has recovered from a viral infection, the cells of the immune system ‘remember’ the virus, and this results in resistance to a second infection by the same virus, known as immunity. However, the strength and length of immunological memory varies between different virus infections and generally wanes as people age. Some people also have a ‘weakened’ immune system, for instance because they are taking medicines which suppress their immune system. This means that they may be less able to resist viral infections, including SARS-CoV-2.

The purpose of vaccines is to stimulate an immune response to potentially serious infections such as SARS-CoV-2, which then builds specific resistance to the infection. This is done by exposing people to harmless subcomponents of the virus, typically by injection. These stimulate the immune system to develop the antibodies and lymphocytes that provide resistance to infection. A head start in the development of a vaccine has been made possible through work on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). This work has also identified some of the potential pitfalls.

So, as with SARS vaccines, the spike protein is once again the main target for vaccine development for the new coronavirus. One objective of a vaccine is to ramp up the human body’s production of antibodies. These stick to the virus and block its ability to bind and enter human cells. In experiments on monkeys, a SARS vaccine based on the whole spike protein produced antibodies to SARS coronavirus and was able to protect the monkeys when they were later infected experimentally.[1]

Stimulating the right parts of the immune system

The human immune system is very delicately balanced. On the one hand it needs to be able to identify and kill viruses and other infectious organisms. On the other hand it is important that an overactive immune response does not damage the healthy tissues of the body. Another feature of the immune system is that it has evolved to be able to fight and protect against a wide variety of infections. For example, lymphocytes that help in immune responses, called helper T cells, come in several varieties. The first (called Th1) kills bacteria and viruses that infect cells; the second (Th2) controls larger parasites like helminths (worms). Activating the wrong pathway can increase the amount of inflammation and worsen the disease.

As part of normal immune responses, lymphocytes and other cells produce immune signalling chemicals called cytokines. These co-ordinate and stimulate immune responses. But if these responses are excessive, they can cause inflammation, which in extreme cases can result in the shut-down of vital organs including the lungs, heart and kidneys. In the case of the SARS virus, there is evidence that this may be responsible for some of the late complications of the disease. In a small percentage of those infected with SARS-CoV-2, an overactive immune response may make an important contribution to the late complications of COVID-19. However, this is not known yet for certain and is an important area for research.

It is therefore essential that vaccines against SARS-CoV-2 stimulate the right balance of immune response and the right pathways to provide protection against infection. For this reason, it will be necessary to undertake careful clinical trials to ensure that new vaccines are extremely safe as well as effective.

Animal models

A further challenge with coronavirus vaccines is the lack of very good animal models for testing.

Following the SARS outbreak in 2003, scientists studied mice. Mice make antibodies in response to SARS infection and their immune system is well understood. But mice do not naturally develop pneumonia with SARS coronavirus infection so it is impossible to test whether a vaccine protects against disease. This can be partially overcome by using older or genetically-modified mice or by modifying the virus.

Hamsters develop lung changes on SARS infection but do not appear to get sick. Ferrets, and several monkey species, develop lung disease with SARS coronavirus but not consistently.[2]

In the case of tests of vaccines against SARS in animal models there were problems in developing both protective immunity and also evidence that the wrong sort of immune response could potentially cause side effects if protection against infection was incomplete. So, in tests of early SARS vaccines in ferrets and monkeys, several vaccines stimulated antibodies against the spike protein but they only protected partially against lung disease.[3] Also, some vaccines were associated with lung inflammation when immunised mice were later infected with the virus.[4]

These examples give some insight into the difficulties of producing vaccines. They show how important it is that vaccines stimulate the right immune responses and why safety tests are vital. But these are typical findings on the route to developing vaccines and there is no reason to think that it will not be possible to develop an effective vaccine to SARS-CoV-2.

Vaccine scientists will exploit existing understanding from SARS and other coronaviruses to fast-track a vaccine for COVID-19 but many challenges lie ahead.

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  1. Bukreyev A, Lamirande EW, Buchholz UJ, et al. Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS. The Lancet. 2004 Jun;363(9427):2122-2127. DOI: 10.1016/s0140-6736(04)16501-x.

  2. Gretebeck LM, Subbarao K. Animal models for SARS and MERS coronaviruses. Current Opinion in Virology. 2015 Aug;13:123-129. DOI: 10.1016/j.coviro.2015.06.009.

  3. Liu W, Fontanet A, Zhang PH, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. The Journal of Infectious Diseases. 2006 Mar;193(6):792-795. DOI: 10.1086/500469.

  4. Tseng CT, Sbrana E, Iwata-Yoshikawa N, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. Plos One. 2012 ;7(4):e35421. DOI: 10.1371/journal.pone.0035421.

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