Intranasal vaccines: a possible way out for coronavirus pandemics

One interesting and also annoying thing about the human immune system is that it’s not a clean, centralized system where you introduce a pattern of antigen into one place and suddenly every T and B lymphocyte in the body knows how to target an intruder. In general, immunity remains limited to specific areas, such as the vascular and lymphatic systems, as well as the intestinal and mucous (nasal) parts of the body.

The result of this is that particular types of vaccines have a different effect, as demonstrated quite succinctly with polio vaccines. The main difference between the oral polio vaccine (OPV) and the inactivated vaccine (injected polio vaccine or IPV) is that the former uses a weakened virus that induces strong immunity in the intestines, which the latter does not. The effect of this is that, although both protect the individual, it does not affect the faecal-oral route of infection of the polio virus, and so the community spreads.

A vaccine works best when it protects the individual, while also preventing new infections as part of so-called sterilizing immunity. This last property is what makes the OPV vaccine so attractive, as it prevents community spread, while IPV is sufficient later, as part of routine vaccinations. The decision to use a vaccine like OPV versus IPV is one of the ways doctors can adjust a population’s protection against a disease.

This is where the current batch of commonly used SARS-CoV-2 vaccines show a major problem, as they do not provide significant immunity to the mucous tissues of the nasal passage, even though this is where the virus initially infects a host, so how from where it replicates and infects others. Here intranasal vaccines can accomplish what OPV did for polio.

Going for the punch

Logically, targeting intranasal (IN) vaccines to address a coronavirus makes a lot of sense, since coronaviruses are among a group of viruses involved in, for example, the common cold. Like rhinoviruses and adenoviruses, they are viruses that are strongly adapted to the respiratory system, just as the polio virus prefers the intestinal tract. Because of this knowledge, multiple intranasal vaccines have been developed and approved, most recently in India and China.

The Chinese vaccine is developed by CanSino Biologics, and is essentially the same as the normal viral vector-based intramuscular (IM) vaccine, except in a form that allows it to be inhaled in a nebulizer. It is approved for use as a booster after a primary course of IM-based vaccination.

The Indian vaccine (BBV154), produced by Bharat Biotech, is intended as a two-dose IN vaccine, rather than just a booster. Both the CanSino and Bharat vaccines are based on a non-replicating adenovirus vector, meaning no special vaccine formulation is needed for the nebulized form. After inhalation of the nebulized vaccine, the adenovirus vector will simply do what it does naturally: enter mucosal cells to deposit its genetic cargo.

These IN vaccines join the Iranian vaccine Razi Cov Pars (three-dose recombinant protein subunit-based vaccine with IN booster), which received emergency use authorization in Iran on October 31 2021. Although large-scale efficacy data are not yet available for any of these vaccines, a recent US study in mice has confirmed that a vaccine based on viral vectors can induce robust immunity. In a 2021 study by Van Doremalen et al. using the ChAdOx1 nCoV-19/AZD1222 viral vector (AstraZeneca) found that IN vaccination of hamsters and macaques prevented large-scale infection and significantly reduced mucosal viral load.

These findings are essentially why scientists in the West are pushing for IN vaccines to be available, with some American scientists, including Eric Topol of Scripps Research, calling for an IN equivalent of Operation Warp Speed ​​​​(OWS) which originally produced the IM vaccines that have been used in Europe and North America since late 2020. The hope is that an IN vaccine approved in the West could counter the continued spread of the SARS-CoV-2 virus amid declining of the effectiveness of IM vaccines against new variants of the virus.

The long journey

Viral infection with and without immunity of the nasal mucosa.  (Credit: Wellford et al., 2022)
Viral infection with and without immunity of the nasal mucosa. (Credit: Wellford et al., 2022)

One aspect of the SARS-CoV-2 virus that is becoming increasingly relevant is the collection of chronic conditions called ‘Long COVID’, which includes blood clots (Knight et al., 2022) and negative neurological outcomes (Xu et al. al. ., 2022). What stands out about such long-term cases of COVID is that it was not necessary for the patient to show severe symptoms of COVID-19, or to have been hospitalized.

The reason for this is likely that, although IM vaccines induce an immune response in the vascular system that often efficiently protects the body’s organs, this does not appear to provide protection for the olfactory epithelium, nor the brain, which they can become infected directly. of the mucous tissues of the nasal passages (Wellford et al., 2022).

Although infection with SARS-CoV-2 provides convalescent (i.e., infection-fighting) immunity within mucosal tissues, this immunity fades over time, like immunity provided by vaccination against SARS-CoV-2. Since every infection carries the risk of permanent damage (and death), the ideal way would seem to be to have an IN boost twice a year (coinciding with the ~6 month drop in efficacy), which can provide a sterilizing immunity.

Basically, this is why IN vaccines are increasingly being considered as a possible way to effectively treat these respiratory viruses, as they should provide much better protection for the individual, while limiting community spread.

Making IN vaccines work

Despite what you might think with three IN vaccines already in licensed (emergency) use, IN vaccines are not very common. Perhaps the most well-known attempt dates back to before the SARS-CoV-2 pandemic, in the form of the FluMist vaccine (LAIV) which to this day is the only FDA-approved IN vaccine. This influenza vaccine is notable for using attenuated influenza virus, rather than the inactivated virus in IM influenza vaccines, and provides comparable efficacy to IM influenza vaccines. Its main attraction is that it avoids the use of needles, and does not require trained personnel to administer the vaccine.

What is challenging with IN vaccine testing is the lack of standardized tests for mucosal immunity. This is largely because IN has not received much attention, which makes conducting large-scale trials of these vaccines and evaluating their effectiveness largely uncharted territory for many regulators. Still, AstraZeneca and other pharmaceutical companies are conducting IN SARS-CoV-2 vaccine trials.

Whether or not an IM vaccine can be adapted to function as an IN vaccine depends primarily on the type. The type of subunit vaccine (eg Razi Cov Pars) likely requires an adjuvant to create a strong enough response, whereas adenovirus-based IM vaccines can be used essentially as is, since as noted above, adenoviruses naturally infect mucosal tissue. . For example, for the AstraZeneca IN vaccine trials currently underway, the challenge appears to be primarily defining efficacy, in the absence of clear protocols and techniques.

Effect of nasal vaccines on the upper and lower respiratory tract for the generation of mucosal and systemic immunity.  (a) Protective immune responses in nasopharynx-associated lymphoid tissue (NALT), with the pathogen-mediated reaction resulting primarily from secretory IgA antibodies generated by mucosal epithelial cells.  (b) Humoral immune response in lower airways with bronchial-associated lymphoid tissue (BALT) with humoral and mucosal/local immune responses.  Abbreviations: CTL, cytotoxic T lymphocyte;  DC, dendritic cell;  NK, natural killer;  TCR, T cell receptor. (Credit: Chavda et al. 2021)
Effect of nasal vaccines on the upper and lower respiratory tract for the generation of mucosal and systemic immunity. (a) Protective immune responses in nasopharynx-associated lymphoid tissue (NALT), with the pathogen-mediated reaction resulting primarily from secretory IgA antibodies generated by mucosal epithelial cells. (b) Humoral immune response in lower airways with bronchial-associated lymphoid tissue (BALT) having both humoral and mucosal/local immune responses. Abbreviations: CTL, cytotoxic T lymphocyte; DC, dendritic cell; NK, natural killer; TCR, T cell receptor. (Credit: Chavda et al. 2021)

Another challenge of IN vaccines is that the nasal mucosal surface provides innate protection against infection by forming a sticky trap that captures potential pathogens (Chavda et al., 2021). This is also why mRNA-loaded liquid nanoparticles as used in IM mRNA vaccines do not appear to be a good match for IN vaccines. Because they rely on the body’s cells producing the target antibody from the mRNA, the lack of an effective way to get the mRNA into the cells is a major obstacle, which the viral vectors by their basic design do not have to cope.

Wait and see

With billions of people worldwide having access to IN SARS-CoV-2 vaccines, there is hope that this could do for the SARS-CoV-2 pandemic what OPV did for polio in the 1950s and 1960s. Depending on the effectiveness of these licensed IN vaccines, some regions and perhaps even nations may find themselves able to declare an end to community spread within a few years, if not less.

Meanwhile, Western drug companies are still conducting their own IN vaccine trials that may yield positive results next year. All of this means that, absent an OWS-like push, Iran, India and China may give us the first glimpses of what the future might look like with IN vaccines against respiratory viruses as soon as next year

With any luck, it may not only provide the long-sought on-ramp to the SARS-CoV-2 pandemic, but also provide IN vaccines with a much-needed R&D boost. After all, who wouldn’t want a twice-yearly nasal spray that protects against even the common cold, or a more effective IN flu shot?

Caption Image: Untitled Lauren Bishop for the Centers for Disease Control and Prevention

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