Why a ‘mucosal’ Covid vaccine has a better shot at ending the pandemic

Novel coronavirus is a pathogen of a ‘mucosal’ organ, different to ‘systemic’ organs. Current vaccines are systemic, and can only reduce disease severity.

A healthcare worker holds up a vial of Covishield vaccine | Representational image: ANI

With several pharmaceutical companies reporting over 90 per cent protection in clinical trials for a Covid-19 vaccine, the world’s hopes of an end to the pandemic have soared. Many countries have already started the massive task of vaccinating entire populations, and others are gearing up.

But the question on everyone’s mind is, are the vaccines going to end the pandemic? We attempt to answer this question by examining past experiences with vaccines for several other viruses, and explain what is expected of a vaccine for a respiratory infection.

The major Covid vaccines available in the market or under evaluation are all administered ‘systemically’. However, only a vaccine designed to induce ‘mucosal’ immune response can protect against respiratory viral infection. Here’s why.

Mucosal versus systemic vaccines

We must first distinguish between two important regions of the body — the systemic and the mucosal compartments. Some internal organs of the body — digestive, respiratory, and genital tracts — are covered with a protective layer of mucous, and are collectively called the mucosal compartment. All the other organs, such as the spleen, liver, blood, and brain, constitute the systemic compartment.

The immune system protects these two compartments differently, primarily because of the presence or absence of ‘microbial flora’. While the systemic organs are sterile, the mucosal region is usually teeming with hordes of commensal (friendly) microorganisms. The immune system can mount a robust response when a pathogenic germ invades any systemic organ, so it’s not a coincidence that the most successful vaccines are primarily directed against systemic infections such as measles, smallpox, chickenpox, etc.

But it’s not that simple when a virus infects the respiratory tract that is already home to billions of microorganisms. Additionally, the mucosal surfaces are also exposed to various harmless proteins ingested via food or inhaled through breathing. The immune system must ignore such innocuous elements by ‘mucosal tolerance’, which also compromises the quality of immune response against a pathogenic organism in the mucosal compartments.

A vaccine must be tailored to protect a specific compartment because cross-protection between systemic and mucosal compartments is either conditional or minimal.

The two forms of the polio vaccine provide an excellent example. The live attenuated oral polio vaccine induces a mucosal immune response, fully protecting the subjects and preventing viral shedding in the faeces. This is how India could eliminate polio.

In contrast, the inactivated polioviral vaccine can generate only a systemic immune response that can reduce disease severity but not prevent viral shedding. Israel had to endure a silent polio outbreak due to its use of the inactivated systemic vaccine, and switched to the oral vaccine to control the spread of the infection.

Why systemic vaccines aren’t enough

A systemic vaccine against a mucosal pathogen may reduce disease severity, but may not impact the infectivity and spreading of the pathogen. The systemic Covid-19 vaccines available or undergoing evaluation will be able to induce IgG antibodies and other protective immune cells in the blood, but are unlikely to induce mucosal IgA antibody production, as demonstrated in the monkey immunisations.

This is because the nature of antibodies generated in these two compartments  — in case of natural infection or by a vaccine — is different. A systemic vaccine injected into the muscles induces the production of IgG antibodies, not IgA antibodies that can block a respiratory virus from attaching to a host cell there. Only a mucosal vaccine can stimulate the production of IgA antibodies.

The IgG antibodies present in the blood can reach the mucosal layers, but this process is inefficient. So even if a high concentration of IgG antibodies is present in the blood after a successful systemic vaccination, sufficient quantities of these antibodies may not reach the upper respiratory tract to prevent viral infection or stop the spread of the viruses to other subjects. For nearly all mucosal infections, the real sign of protection is the presence of elevated IgA levels in the respiratory compartment.

Although mucosal vaccines can elicit IgA antibodies, these vaccines suffer from a limitation — that mucosal responses induced by them usually are not long-lasting.

This limitation may be ascribed to two different reasons. First, the contact between respiratory viruses such as the new coronavirus and rhinoviruses and the body is typically short and minimal — usually one or two weeks. The short duration of exposure is insufficient for the host to develop a robust immune response. In contrast, the body can develop powerful immune responses to chronic viruses, such as HIV or Hepatitis B viruses, because these viruses stay with the host for years.

The second reason is rapid replacement of the memory cells in the mucosal tissues. In the systemic compartments, the duration of immune response is dependent on how long a few memory cells are stored in local tissues and bone marrow. In mucosal compartments, immune memory exclusively relies on the memory cells preserved in the mucosal tissues, not in the bone marrow. The friendly microorganisms in mucosal surfaces have to be controlled by the immune system so that they don’t become injurious. As the composition of these microorganisms changes regularly and dynamically, the memory cell repertoire stored in the mucosal tissues also must be replaced at a comparatively rapid rate.

Three-level protection

What do we expect a protective Covid vaccine to do? A good Covid vaccine must protect at three different levels. First, the vaccine must induce IgA antibodies in the upper respiratory tract where the coronavirus attaches initially and prevent viral infection. The virus subsequently spreads to the lower respiratory tract and the lungs. We need a combination of IgA and IgG antibodies to stop the viral expansion to the lungs, which only a mucosal, but not a systemic, vaccine can do.

Second, in a minority of subjects, the virus can disseminate to systemic body organelles, such as the brain, gut, liver, heart, etc. A systemic vaccine can minimise disease severity by preventing viral dissemination. Lastly, the virus will spread to other subjects through aerosol droplets generated in the upper respiratory tract. Only IgA antibodies can prevent the shedding of viral particles by this route.

The reported protective efficacy of the Covid vaccines is controversial, given the limitations of the study design and evaluation procedures. A combination of mucosal and systemic vaccines may be necessary to protect an infected subject, minimise the disease severity, and prevent viral expansion in a population.

Udaykumar Ranga is a professor of virology at Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru. Arun Panchapakesan is a PhD student working under him. Views are personal.