Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4+ and CD8+ T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4+ and CD8+ T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4+ and CD8+ T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pan-coronavirus vaccine to protect against past, current, and future outbreaks.

(2009). New concepts in herpes simplex virus vaccine development: notes from the battlefield. Expert Review of Vaccines: Vol. 8, No. 8, pp. 1023-1035.

HSV type 1 (HSV-1) is a prevalent human pathogen that infects >3.72 billion individuals worldwide and can cause potentially blinding recurrent corneal herpetic disease. HSV-1 establishes latency within sensory neurons of trigeminal ganglia (TG), and TG-resident CD8⁺ T cells play a critical role in preventing its reactivation. The repertoire, phenotype, and function of protective CD8⁺ T cells are unknown. Bolstering the apparent feeble numbers of CD8⁺ T cells in TG remains a challenge for immunotherapeutic strategies. In this study, a comprehensive panel of 467 HLA-A*0201–restricted CD8⁺ T cell epitopes was predicted from the entire HSV-1 genome. CD8⁺ T cell responses to these genome-wide epitopes were compared in HSV-1–seropositive symptomatic individuals (with a history of numerous episodes of recurrent herpetic disease) and asymptomatic (ASYMP) individuals (who are infected but never experienced any recurrent herpetic disease). Frequent polyfunctional HSV-specific IFN-γ⁺CD107^a/b+CD44^highCD62L^lowCD8⁺ effector memory T cells were detected in ASYMP individuals and were primarily directed against three “ASYMP” epitopes. In contrast, symptomatic individuals have more monofunctional CD44^highCD62L^highCD8⁺ central memory T cells. Furthermore, therapeutic immunization with an innovative prime/pull vaccine, based on priming with multiple ASYMP epitopes (prime) and neurotropic TG delivery of the T cell–attracting chemokine CXCL10 (pull), boosted the number and function of CD44^highCD62L^lowCD8⁺ effector memory T cells and CD103^highCD8⁺ tissue-resident T cells in TG of latently infected HLA-A*0201–transgenic mice and reduced recurrent ocular herpes following UV-B–induced reactivation. These findings have profound implications in the development of T cell–based immunotherapeutic strategies to treat blinding recurrent herpes infection and disease.

The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally “protected” exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4⁺and CD8⁺T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation “asymptomatic” clinical herpes vaccines, and discuss future mucosal “asymptomatic” prime-boost vaccines that could optimize local protective immunity.

Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin‐producing pancreatic β cells by autoreactive T cells. The polygenic trait for T1D risk implicates many genes that have an impact on fundamental immunological processes such as central and peripheral tolerance. Several pieces of evidence have suggested that many of the genetic loci that are directly linked to type 1 diabetes susceptibility modulate the generation and/or the activation of autoreactive T‐lymphocytes. We and others have proposed a critical role for medullary thymic epithelial cells (mTEC) forming the Hassall’s corpuscles in T‐cell tolerance. Indeed, mTEC have been found to express promiscuous self‐antigens, used directly or through thymic dendritic cells to drive either negative selection of insulin‐reacting precursors or their differentiation into naturally occurring regulatory Foxp3⁺ CD4⁺ CD25⁺ T cells. In the periphery, naturally occurring Foxp3⁺ CD4⁺ CD25⁺ regulatory T (Treg) cells represent the master cells in dominant peripheral T‐cell tolerance. The development and function of Treg cells are ultimately linked to IL‐2 and Foxp3 expression. This review addresses recent literature and emerging concepts of central and peripheral T‐cell tolerance with regards to T1D.