Are nasal-spray vax the solution to respiratory infectious diseases?

A recent study published in the journal Trends in Molecular Medicine reviewed the current efforts in developing nasal vaccines, delivery systems, and clinical applications for preventing respiratory illnesses.

Introduction
Mucosal surfaces are exposed to external environments and serve as primary entry sites for foreign antigens. Thus, they have a unique immune system that is independently regulated, which acts as the first barrier against foreign substances. Mucosal vaccines leverage this unique system and have been in the limelight due to the coronavirus disease 2019 (Covid-19) pandemic.

Though intramuscularly (IM) administered mRNA vaccines have been effective, they fail to elicit mucosal immunity efficiently. In contrast, mucosal vaccines induce systemic responses at par with IM-administered vaccines and trigger responses at mucosal surfaces. As a result, mucosal vaccination can protect against infection and severe illness. In addition, mucosal immune responses are generally induced at antigen delivery/administration sites.

Multiple administration sites have been considered for mucosal vaccines, such as oral, vaginal, rectal, and nasal mucosa. Nasal administration elicits effective responses in the reproductive and respiratory tracts through the lymphocyte-homing pathway. Therefore, it is suggested as an effective and logical means to prevent respiratory and sexually-transmitting infections, including Covid-19.

Mucosal immune responses
Nasopharyngeal-associated lymphoid tissue (NALT) is a primary site of immune induction for vaccines and invading pathogens. NALT contains B, T, and antigen-presenting cells (APCs) and is covered by a layer of microfold cells, specialized cells for antigen uptake. APCs phagocytose the absorbed antigens, process and present them to naïve T cells.

Stimulated T lymphocytes produce interleukin (IL)-5 and transforming growth factor (TGF)-β for B cell activation. Then, B cells differentiate into immunoglobulin (Ig) A-positive (IgA+) B cells. The antigen-specific T and IgA+ B cells traverse to effector sites, where the IgA+ B cells terminally differentiate into plasma cells producing IgA.

The plasma cell-produced polymeric or dimeric IgA binds to the polymeric Ig receptor on epithelial cells and is transported as secretory IgA (sIgA) into the nasal cavity lumen. sIgA is pivotal in mucosal immunity for capturing upper respiratory tract pathogens and preventing adhesion to mucosal surfaces.

A critical feature of acquired immune responses is the induction of immunologic memory for long-term immunity against infection. Tissue-resident memory cells remain in non-lymphoid mucosal tissues without entering circulation for long periods. These cells are activated upon re-exposure to antigens and promptly induce effector functions.

Nasal vaccine delivery systems
Mucosal tissues have mechanisms to exclude foreign particles, which may prevent the efficient delivery of vaccine antigens. Therefore, a delivery vehicle that can circumvent this obstacle is necessary. To this end, non-replicating and replicating delivery systems have been developed. Replicating systems involve recombinant viral vectors that multiply in the host and deliver vaccine antigens continuously.

Besides viruses, bacteria-based delivery systems have been investigated. Specifically, Lactobacillus, a relatively safe organism, is a leading candidate for vaccine delivery due to its ability to deliver vaccine antigens directly to the nasal mucosa. Although effective in inducing humoral and cellular responses, the safety concerns of replicating delivery systems, such as the toxic effects of vectors and the reversion to virulence, need to be addressed before these systems can advance in clinical use.

Non-replicating delivery systems, such as non-replicating viral vectors, polymers, nanomaterials, and liposomes, have been developed to overcome the safety issues associated with replicating designs. Adenoviral vectors are promising as they do not require adjuvant co-administration. Nanomaterials have been extensively studied as vaccine delivery vehicles due to biological affinity and safety advantages.

Covid-19 nasal vaccines
Eleven nasal vaccine candidates are being tested in clinical trials, per the World Health Organization’s Covid-19 vaccine tracker. The replication-competent influenza virus vector-borne vaccine based on the spike protein’s receptor-binding domain is in a Phase 3 trial. Non-replicating vector-borne vaccines under various clinical trial stages include CVXGA1-001, BBV154, and Covishield.

COVI-VAC, a live-attenuated vaccine under phase 3 evaluation, has improved safety due to the deletion of the furin cleavage site and the recoding of spike segments. The MV-014-212 vaccine, based on the spike protein, uses a live-attenuated respiratory syncytial virus (RSV) vector and is evaluated in a phase 1 trial for safety and immunogenicity. Besides vector- and live-attenuated virus-based vaccines, three recombinant protein subunit-based nasal vaccines, CIGB-669, Razi Cov Pars, and ACM-001, are under development.

Concerns with the clinical applications of nasal vaccines
FluMist Quadrivalent is the only nasal influenza vaccine approved by the United States (US) Food and Drug Administration (FDA). Even if a cold-adapted attenuated vaccine could be developed by decreasing virulence, it will not be approved for use in older adults and infants, as nasal administration of live vaccines can result in medically significant wheezing.

Another critical concern is the reversion to the replicative state of vaccines using the whole pathogen. As such, recombinant protein subunit-based vaccines appear safer than live vaccines. Nevertheless, recombinant antigens require delivery systems and tend to induce weak responses, warranting co-administration of adjuvants as immunostimulants. For example, an inactivated nasal influenza vaccine was used in Switzerland in the past but was terminated due to several cases of facial nerve palsy.

Furthermore, another inactivated nasal influenza vaccine (Pandemrix) increased the risk of narcolepsy. Nasally administered substances may traverse into the brain via the olfactory epithelium and bulbs, potentially affecting neural functions. Because of the nasal cavity’s proximity to the central nervous system (CNS), nasal vaccine candidates must be tested before clinical application to ensure that vaccine components do not affect the CNS.

Concluding remarks
Nasal vaccines can elicit antigen-specific systemic and mucosal immune responses and are considered viable alternatives to IM vaccines, given their efficacy and ease of administration. However, only a few nasally administered vaccines are in use currently. A concerted global effort to develop safe and effective nasal vaccines is necessary to combat the Covid-19 pandemic and the threat of pandemics in the future. Medical News