The impact of immuno-aging on SARS-CoV-2 vaccine development

Abstract

The SARS-CoV-2 pandemic has almost 56 million confirmed cases resulting in over 1.3 million deaths as of November 2020. This infection has proved more deadly to older adults (those >65 years of age) and those with immunocompromising conditions. The worldwide population aged 65 years and older is increasing, and the total number of aged individuals will outnumber those younger than 65 years by the year 2050. Aging is associated with a decline in immune function and chronic activation of inflammation that contributes to enhanced viral susceptibility and reduced responses to vaccination. Here we briefly review the pathogenicity of the virus, epidemiology and clinical response, and the underlying mechanisms of human aging in improving vaccination. We review current methods to improve vaccination in the older adults using novel vaccine platforms and adjuvant systems. We conclude by summarizing the existing clinical trials for a SARS-CoV-2 vaccine and discussing how to address the unique challenges for vaccine development presented with an aging immune system.

Keywords: (4–6): SARS-CoV-2; Adjuvants; Aging; Vaccine delivery platforms; Vaccines.

Fig. 1

Cell-specific changes of the innate and adaptive human immune system associated with aging. The effects of aging in various cell types are depicted. With aging, dysregulated innate immune responses can result in failure to efficiently respond to pathogens and vaccines. The production of PAMPs and DAMPs that arise from chronic viral infections and cell damage contributes to the elevated pro-inflammatory state, also known as “inflammaging.” During inflammaging, increased basal levels of pro-inflammatory cytokines are partially a result of dysregulated PRR signaling including TLRs, RIG-I, cGAS-STING, and inflammasome pathways. This increased basal activation in cell types such as monocytes, macrophages, and dendritic cells restricts sensitivity to new pathogens and responses to vaccines, resulting in dysregulated innate immunity and failure to progress to productive adaptive response. Changes in overall TLR protein expression have been reported with other studies reporting on specific cell subsets that expression levels remain the same, but alterations in intracellular signaling proteins like PI3K and MAPK levels decreased. The failure to progress to adaptive immunity takes the form of the overall decline in T and B cells with a reduction in TCR diversity and expansion and a progressive shift to Th2 immunity. The levels of AID, important for class switch recombination, are reduced in B cells, possibly contributing to the poor memory B cell and antibody formation and a decreased response to vaccination. PAMPs, pathogen-associated molecular patterns; and DAMPs, damage-associated molecular patterns; PRR, pattern recognition receptor; TLR, toll-like receptor; RIG-I, retinoic acid-inducible gene I; cGAS-STING, cyclic GMP-AMP Synthase; IFN, interferon; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; TCR, T cell receptor; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; TCR, T cell receptor; Th2, T helper type 2 cell; AID, activation-induced cytidine deaminase

Fig. 2

Ongoing vaccine development platforms for SARS-CoV-2 (live attenuated, nucleic acid, viral vector, and protein vaccines. a Candidate vaccines in clinical trial. mRNA-1273 created by Moderna Inc./NIAID/CEPI is now in phase 3 (NCT04470427). Each participant will receive 2 IM100ug doses 28 days apart or placebo; BioNTech/Pfizer BNT162 is now in phase 3 (NCT04368728). Each participant will receive 2 IM mid dose injections 21 days apart or placebo; INO-4800 by Inovio/Wistar Institute is now in Phase 2/3 (NCT0464263). Each participant will receive 2 ID injections (1 mg/dose) 28 days apart or placebo; AZD1222 by AstraZeneca is now in phase 3 (NCT04516746). Each participant will receive 2 IM injections (5e¹⁰ vp/dose) 4 weeks apart or placebo; LV-SMENP by Shenzhen Medical Institute is now in phase 1 (NCT04276896). Each participant will receive 5e⁶ LV-DCs (ID) +1e⁸ antigen-specific CTLs (IV)/dose. Ad5-nCoV by CanSino Biologics is now in phase 3 (NCT04526990). Each participant will receive 1 IM injection or placebo; NVX-CoV2373 by Novavax is now in phase 3 (NCT04611802). Each participant will receive 2 IM injections (5 μg vaccine +50μg Matrix-M1 adjuvant/dose) 21 days apart or placebo; bacTRL-Spike by Symvivo is now in phase 1 (NCT04334980). Each participant will receive either (1) a single dose of bacTRL-Spike, equivalent to 1 billion colony forming units (cfu) of B. longum; or (2) a single dose of bacTRL-Spike, equivalent to 3 billion cfu of B. longum; or (3) a single dose of bacTRL-Spike, equivalent to 10 billion cfu of B. longum. b Preclinical vaccine candidates’ platforms (live attenuated virus, inactivated virus, replicating/non-replicating viral vector, virus like particles, subunit, and nucleic acid vaccine) *Vaccines are the frontrunners in development as of 11/30/2020. ID, intradermally; IM, intramuscular; EP, electroporation; VP, viral particles; NIAID, National Institute of Allergy and Infectious Diseases; CEPI, Coalition for Epidemic Preparedness Innovations