The benefits of developing COVID-19 vaccines delivered in an intranasal mist

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A microbiologist and an immunologist from the University of Alabama at Birmingham have published a Perspective piece in the journal Science outlining the possible benefits of developing COVID-19 vaccines delivered in an intranasal mist rather in the arm as an injection.

 In their paper, Frances Lund and Troy Randall suggest that nasal applications provide a host of benefits that injections do not.

The researchers begin their arguments by noting that the SARS-COV-2 virus is transmitted through the air and infects the nasal passages and then lungs, which raises the question:

Why are only seven of the 100 vaccines currently under development or in use, delivered intranasally?

They note that intranasal vaccines have three obvious advantages: They are needle-free, they can deliver drugs directly to infected sites, and they can elicit mucosal immunity in the lungs.

The researchers also note that use of nasal vaccines is not new; flu vaccines have been administered intranasally for decades. They also point out that prior research has shown that both nasal infections and vaccinations can instigate an immunoglobulin A (IgA) response in both serum and in the respiratory system – intramuscular administration, on the other hand, can only do so for serum fluids.

They also note that CD8+ T cells can be primed by nasal vaccines to express receptors, making them ready to fight an infection. They note also that IgA and T and B cells in the respiratory system can provide a barrier of sorts against infections when stoked by an intranasally administered vaccine.

Lund and Randall also argue that some of the nasal vaccines in development have been shown to set off long-lasting virus-neutralizing responses in immune system cells – some have also been shown to help protect against weight loss and pneumonia associated with viral infections.

And they note that during testing, animals given an intranasally administered vaccine versus an intramuscular vaccine had reduced levels of viral shedding and replication, both in nasal passages and in the lungs.

The researchers acknowledge that prior research has shown that intranasally administered vaccines do suffer from a couple of flaws. First, intranasally administered vaccines involve the use of live attenuated viruses, which carries some risk of infection.

Second, they do not provide the same degree of immune longevity as those administered in the muscle. They conclude that, ultimately, the best solution may be to use both types of vaccinations – one to give the body immediate protection, the other to keep the body safe longer.

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First reported in late 2019 in China (Zhu et al., 2020), infection caused severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic in just a few months. As of 5 October 2020, the World Health Organization estimates 34.8 million cases of coronavirus disease 2019 (COVID-19) worldwide, with 1,030,738 associated deaths (WHO. 2020a).

Moreover, morbidity from SARS-CoV-2 infection can be severe, especially in high-risk groups (e.g., elderly, persons with chronic comorbidities such as hypertension, obesity, and diabetes) (CDC, 2020a). Early evidence from COVID-19 survivors and survivors of similar β-coronaviruses such as SARS and Middle East respiratory syndrome (MERS), suggests that COVID-19 survivors may suffer long-term sequela (e.g., inflammation of and damage to lungs and heart muscle) (Advisory Board, 2020).

Taken together, the reach of infection and its impact on human health and well-being underscore the immediate need for safe and effective vaccines against SARS-CoV-2 to end this pandemic and prevent its return.

Despite the well-recognized role of mucosal immunity in prevention of disease (reviewed in Van Ginkel et al., 2000 and Holmgren et al., 2005), most of the COVID-19 vaccines in clinical testing are administered via intramuscular injection (Funk et al., 2020, WHO 2020b) – a route that elicits systemic immunity without inducing mucosal immune responses.

The lack of mucosal immunity may limit the utility of intramuscularly administered COVID-19 vaccines, given that transmission of SARS-CoV-2 is primarily via respiratory droplets released by infected individuals in enclosed spaces (CDC, 2020b), with the nose and other portions of the respiratory mucosa being the primary routes of entry (Li et al., 2020).

The nasal compartment shows particular susceptibility to SARS-CoV-2 infection due to abundant co-expression of the viral entry receptor (angiotensin-converting enzyme-2, ACE-2) and a required activating protease (TMPRSS2) in nasal goblet and ciliated cells (Sungnak et al., 2020).

These cells are thought to be the most likely initial infection route for the virus and it is hypothesized that the nasal cavity serves as the initial reservoir for subsequent seeding of the virus to the lungs (Hou et al., 2020).

The well-documented association of anosmia with COVID-19 further supports the nasal cavity as a principle reservoir of infection (Brann et al., 2020), and presence of high viral load in the nasal cavity may facilitate transmission of the virus. In contrast to intramuscular injection, mucosal vaccination via the intranasal route has the potential to confer sterilizing immunity in the respiratory tract (Hassan et al., 2020), reducing virus-induced disease and transmission of COVID-19.

Entry of SARS-CoV-2 into host cells depends on binding of the receptor-binding domain (RBD) of the spike protein to ACE-2, leading to fusion of the virus with the cell membrane (reviewed by Letko et al., 2020), and in human convalescent serum the majority of neutralizing antibodies are directed against RBD (Seydoux et al., 2020, Premkumar et al., 2020).

While most clinically advanced SARS-CoV vaccine candidates deliver the trimeric spike ectodomain as the target antigen (Funk et al., 2020, WHO 2020b), subdomains of spike such as S1 and RBD represent alternative vaccine antigens for stimulating of a more focused immune response against these well-conserved domains, while limiting the induction non-functional antibodies and the risk of enhanced respiratory diseases (ERD).

Here, we report results of preclinical immunogenicity testing of AdCOVID, an intranasal replication-deficient Ad5-vectored vaccine candidate against COVID-19 that encodes the RBD from SARS-CoV-2 spike protein. Immunogenicity of the vaccine was assessed following a single administration in two strains of mice by measuring the induction of spike-specific antibody levels in sera and bronchoalveolar lavage (BAL) fluids.

Functionality of these vaccine-elicited antibodies was measured in live virus neutralization assays. In addition to the induction of robust neutralizing antibody responses and mucosal IgA against SARS-CoV-2, the RBD vaccine candidate stimulated systemic and mucosal cell-mediated immune responses characterized by a T-helper 1 (Th1) type cytokine profile and through the induction of cytokine-producing CD4+ and CD8+ T cells, including lung-resident memory T (Trm) cells. These data, which demonstrate the immunogenicity of AdCOVID, support development of this candidate vaccine in response to the serious global health threat.

Reference link : https://www.biorxiv.org/content/10.1101/2020.10.10.331348v1.full

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More information: Frances E. Lund et al, Scent of a vaccine, Science (2021). DOI: 10.1126/science.abg9857

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