![]() ![]() T follicular helper (T FH) cells help S protein-specific B cells to differentiate into antibody-secreting plasma cells and promote the production of high affinity anti-S protein antibodies. The resultant activated DCs present antigen and co-stimulatory molecules to S protein-specific naive T cells, which become activated and differentiated into effector cells to form cytotoxic T lymphocytes or helper T cells. RNA sensors such as Toll-like receptor 7 (TLR7) and MDA5 are triggered by the mRNA vaccines, and TLR9 is the major double-stranded DNA sensor for the AdV vaccine. In addition, innate sensors are triggered by the intrinsic adjuvant activity of the vaccines, resulting in production of type I interferon and multiple pro-inflammatory cytokines and chemokines. The two vaccine formulations - mRNA encoding the SARS-CoV-2 spike (S) protein encapsulated in lipid nanoparticles or adenovirus (AdV) vectors encoding the S protein - gain entry into dendritic cells (DCs) at the injection site or within lymph nodes, resulting in production of high levels of S protein. Once in the LN, the LNP is engulfed by dendritic cells (DCs), which subsequently produce and present the antigen to T cells for activation of the adaptive immune response. The LNP carrier further protects the mRNA, can target delivery to lymphatics and promote protein translation in lymph nodes (LNs) 7. The current vaccines contain purified, in vitro-transcribed single-stranded mRNA with modified nucleotides to reduce binding to TLR and immune sensors, thus limiting excessive production of type I interferon and its inhibitory function on cellular translation (see ref. Endosomal Toll-like receptors (TLR3 and TLR7) bind to ssRNA in the endosome, while components of the inflammasome such as MDA5, RIG-I, NOD2 and PKR bind to ssRNA and dsRNA in the cytosol, resulting in cellular activation, and production of type I interferon and multiple inflammatory mediators 7 (Fig. Upon entry into cells, single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) are recognized by various endosomal and cytosolic innate sensors that form a critical part of the innate immune response to viruses. For mRNA vaccines, the mRNA can serve as both immunogen (encoding the viral protein) and adjuvant, owing to intrinsic immunostimulatory properties of RNA. An optimal adjuvant stimulates innate immunity without inducing systemic inflammation that could elicit severe side effects. ![]() To stimulate adaptive immunity, a vaccine requires a pathogen-specific immunogen as well as an adjuvant - the latter stimulates the innate immune system and provides the necessary second signal for T cell activation. ![]() Thus, we still have much to learn about how these vaccines mobilize the immune response, the durability of protection and how to further optimize them to protect against new variants, strains and disease manifestations. While the AdV vaccine platform has been licensed for Ebola, the mRNA vaccine platform represents a newly licensed formulation. These trials, which collectively involved more than 100,000 participants, provide compelling rationale for expedient and widespread vaccination of the global population. Both vaccine types generate significant neutralizing antibody titres and virus-specific T cell responses as measured in blood 2–4 weeks post inoculation 5, 6. To date, results from the phase III clinical trials showed that both the Pfizer/BioNTech (BNT162b2) and Moderna (mRNA-1273) mRNA vaccines achieved 90–95% efficacy in protecting against COVID-19 (refs 1, 2), while the AdV vaccines (ChAdOx1 nCoV-19) and Gam-COVID-vac (Sputnik V) showed protection at a slightly lower efficacy (average 70% and 91%, respectively) 3, 4. Both the mRNA and AdV vaccines encode production of the SARS-CoV-2 spike (S) protein, which is the primary target for neutralizing antibodies generated from natural infection and for therapeutic monoclonal antibodies 1. The approved vaccines developed by Pfizer and Moderna use mRNA technology and lipid nanoparticle (LNP) delivery systems, while the approved formulations by AstraZeneca, Johnson and Johnson and Gam-COVID-vac (Sputnik V) contain DNA delivered within non-replicating recombinant adenovirus (AdV) vector systems 1, 2, 3, 4. Significant advances in cutting edge vaccine technologies over the past decade have resulted in two main types of SARS-CoV-2 vaccines now being approved for emergency use - an unprecedented achievement in modern medical science.
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