Study: Delivery Routes for COVID-19 Vaccines. Image Credit: strannik65 / Shutterstock

Could the intranasal route be an alternate avenue of COVID-19 vaccination?


The coronavirus disease 2019 (COVID-19) pandemic has exacted an enormous toll on public health and the economy in many parts of the world. The causal agent of the pandemic is the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many vaccine candidates have been developed, but the delivery of vaccines is presently limited to intramuscular vaccination (also known as ‘jabs’ or ‘shots’).

A new study has been published in the journal Vaccines that summarizes the history of vaccines, reviews the current progress in COVID-19 vaccine technology, and discusses the status of intranasal COVID-19 vaccines as a potential pathway to immunization.

Study: Delivery Routes for COVID-19 Vaccines. Image Credit: strannik65 / Shutterstock

Decoding the body’s immune responses to SARS-CoV-2 infection is essential to design new vaccines. SARS-CoV-2 binds to target cells through the angiotensin-converting enzyme (ACE2) receptor. Once SARS-CoV-2 enters the body, an array of pattern recognition receptors (PRRs) sense viral infection. This, subsequently, brings about phosphorylation of Interferon Regulatory Factor 3 (IRF3) and IRF7. IRF3 and IRF7 regulate type I interferon (IFN) and interferon-stimulated genes (ISGs).

SARS-CoV-2 induces low-level type I and II IFNs and also brings about the release of proinflammatory cytokines and chemokines. The activation of the immune response is crucial to fight the infection. But, the overproduction of pro-inflammatory cytokines, also known as a “cytokine storm,” has the potential to cause tissue damage and is often observed in critically ill patients.

COVID-19 patients show lymphopenia, with decreased CD4 T, CD8 T, and B cells, and the degree of lymphopenia is much more severe and persistent than other viral infections. CD8 T cells from COVID-19 patients express more inhibitory receptors (PD-1 and TIM-3), and these receptors correlate with terminal differentiation and functional cell exhaustion. CD4 T cells show similar properties as CD8 T cells.

Interestingly, some individuals unexposed to SARS-CoV-2 have SARS-CoV-2-specific CD4 T cells. The CD4 T cells cross-react with common cold viruses. This protective immunity lasts 12 months, and the potential benefits of this cross-reactivity should be examined in future research.

Currently, more than 100 vaccines have already been or are being tested in clinical trials. Traditionally, vaccines are either attenuated or inactivated pathogens or protein subunits from the pathogen. Attenuating strains can take years, and there are also safety concerns. To alleviate these concerns, pathogens inactivated by heat, radiation, or chemical treatment have been developed as vaccines. Attenuated pathogens can become more virulent, and people with comorbidities might be susceptible to the attenuated strain. Despite these limitations, in the current context, live attenuated vaccines (COVI-VAC and Codagenix) have been developed, and they have the advantage that they generally do not require adjuvants. In case adjuvants are required, aluminum hydroxide is commonly used. BBIBP-CorV and Corona Vac are two examples of such vaccines requiring the adjuvant.

Protein subunit vaccines contain viral proteins and are considered safer. However, they require adjuvants and booster shots (NVX CoV2373 and ZF2001). Viral vectors, including adenoviruses, have been used successfully to produce vaccines against pathogens such as the Ebola virus. However, some patients may have immunity against the viral vectors.

To avoid pre-existing immunity, AstraZeneca and Oxford used a chimpanzee adenovirus to deliver the gene for the S protein (ChAdOx1, AZD1222). The pandemic has led to the development of a host of DNA and RNA vaccines. Antigen-coding DNA is delivered intradermally or intramuscularly and electroporated for effective delivery into cells. RNA vaccines have been at the forefront of the current COVID-19 pandemic. mRNA-1273, which is currently in use as the “Moderna” vaccine, has shown an efficacy of 94.1%. Pfizer and BioNTech produced BNT162b2, two doses of which showed 95% protection.

Most vaccines are injected intramuscularly. The route of immunization may induce different mechanisms of protection. Also, different vaccine platforms, such as mRNA, DNA, or an adenoviral vector vaccine, bring about varied efficacy.

Recent studies have indicated that local vaccination might be more effective than other vaccination methods for mucosal infection. Mucosal vaccination does not involve needles and, hence, is safer as it eliminates the risk of blood-borne infections. There are some limitations of mucosal vaccination, though. Little is known about mucosal immunity. Antigens could be destroyed by proteolytic enzymes making their absorption difficult.

Additionally, adjuvants might be necessary, and some studies have shown that alum, which is a commonly used adjuvant, failed to IgG and IgA and recruitment of T and B cells to the mucosal area. Since SARS-CoV-2 mainly infects the upper respiratory tract, the environment of the nasal passage is important for immunity.

Many recent experiments on nasal vaccines have yielded positive preliminary results, but the results are as yet inconclusive. Although, the efficacy of intranasal vaccines may depend on the dosage or the vaccine platform; they might be an effective route to attain herd immunity because they prevent an interhuman response. Several clinical trials of intranasal vaccines, including (e.g., AdCOVID), are being conducted. More research is needed to determine the most effective route for immunization.



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