Delivery Routes for COVID-19 Vaccines

Abstract

The novel coronavirus, SARS-CoV-2, which causes COVID-19, has resulted in a pandemic with millions of deaths. To eradicate SARS-CoV-2 and prevent further infections, many vaccine candidates have been developed. These vaccines include not only traditional subunit vaccines and attenuated or inactivated viral vaccines but also nucleic acid and viral vector vaccines. In contrast to the diversity in the platform technology, the delivery of vaccines is limited to intramuscular vaccination. Although intramuscular vaccination is safe and effective, mucosal vaccination could improve the local immune responses that block the spread of pathogens. However, a lack of understanding of mucosal immunity combined with the urgent need for a COVID-19 vaccine has resulted in only intramuscular vaccinations. In this review, we summarize the history of vaccines, current progress in COVID-19 vaccine technology, and the status of intranasal COVID-19 vaccines. Future research should determine the most effective route for vaccine delivery based on the platform and determine the mechanisms that underlie the efficacy of different delivery routes.

Keywords: COVID-19; SARS-CoV-2; mucosal vaccine; vaccine.

Figure 1

Immune responses against SARS-CoV-2 infection. (A) SARS-CoV-2 can be sensed by pattern recognition receptors (PRRs) such as Toll like receptors and RIG-I like receptors. Viral sensing induces interferons and proinflammatory cytokines and chemokines. However, SARS-CoV-2 inhibits induction of interferons. Reduced interferons and excessive proinflammatory cytokines cause cytokine storm and severe inflammation. (B) Innate immune cells including monocyte, macrophage, and neutrophils are the main source of proinflammatory cytokines such as IL-6 and TNF. Cytokines further activate immune cells. Unconventional T cells (MAIT cells, γδ T cells) also participate in positive feedback loop of inflammation. (C) SARS-CoV-2 infection leads to lymphopenia. CD8 T cells from COVID-19 patients showed exhausted feature. Whether these features represent activation or exhaustion should be addressed. Furthermore, balance among CD4 T cell subsets is a critical factor for disease severity. (D) Antibodies from B cells neutralize virus entry. Mucosal IgA is rapidly produced and shows superior neutralizing capacity compared to systemic IgG while circulating IgA is correlated with severe disease symptoms. Circulating IgG systemically protects host from virus. Figure was created by biorender.com (BioRender, Toronto, ON, Canada).

Figure 2

Vaccine platforms for COVID-19. (A) Live attenuated vaccines are developed through repeated attenuation. Inactivated vaccines are generated by chemical or heat stress. Live attenuated vaccines do not require adjuvant. However, this technology takes a long time and has safety concerns. Inactivated vaccines have reduced danger compared to attenuated vaccines. However, they need adjuvant because they lose their immunogenicity. (B) Protein subunit vaccine or subunit-containing virus like particle (VLP) provides antigen to antigen presenting cells (APCs). APCs present antigen to immune cells and generate immune memory. Although these platforms are safe, they need adjuvant. (C) Viral vector vaccines deliver antigen-coding genes to target cells. Infected cells make and give antigen to APCs. Viral vectors do not need adjuvant because the vector itself is danger-associated molecular pattern (DAMP). Delivery is also easy. However, they have safety concerns and vectors can be eradicated by host immune memory if the host has experience of the viral vector. mRNA vaccine and DNA vaccine deliver mRNA and DNA to the target cells. mRNA and DNA generate antigens. While mRNA vaccines are safe, fast and cheap, they need “cold chain” because RNA is unstable. DNA vaccines are stable and safe. However, they are weak to induce proper immunity. Figure was created by biorender.com (BioRender, Toronto, ON, Canada).

Figure 3

Intramuscular vaccination induces systemic immune response including lower respiratory tract (LRT), but not upper respiratory tract (URT). In contrary, intranasal vaccination induces local immune response in LRT with systemic immunity. Local immunity prevents nasal shedding of viruses which is critical for herd immunity. In the mucosal area, delivered antigens can be degraded by proteolytic enzymes. Mucosal homeostasis inhibits immune response against vaccines. Figure was created by biorender.com (BioRender, Toronto, ON, Canada).