Researchers from UC San Diego developed an invention that enables protein expression to be upregulated using specific proteins and/or peptide sequences derived from SARS-CoV-2 proteins that are engineered to recognize specific mRNA transcripts by fusion to RNA-targeting modules such as CRISPR/Cas systems. They anticipate that these proteins can be fused or tethered to any engineered RNA-targeting moiety/module such as PUF/Pum, and pentatricopeptide proteins.

Following the pandemic, there is a clear need for improved technology in the area of vaccines. A pressing challenge is to enable a rapid response to emerging threats, using an established platform technology.

Streptococcus pyogenes (group A Streptococcus [GAS]) is a leading health and economic burden worldwide, with an estimated 700 million infections occurring annually. Among these are 18.1 million severe cases that result in over 500,000 deaths. Despite active research, a protective vaccine remains elusive, leaving antimicrobial agents as the sole pharmacological intervention against GAS. To date, penicillin remains a primary drug of choice for combating GAS infections. However, despite no apparent emergence of resistant isolates, the rate of treatment failures with penicillin has increased to nearly 40% in certain regions of the world. Due to the high prevalence of GAS infection and the decreasing efficacy of the available repertoire of countermeasures, it is critical to investigate alternative approaches against GAS infection. An emerging strategy for combating pathogenic bacteria involves targeting virulence. To avoid immune clearance, GAS expresses a wide variety of secreted and cell-associated virulence factors to facilitate survival during infection. Despite decades of inquiry into the role and regulation of GAS virulence factors, the function and potential importance of many proteins involved in pathogenicity remain unknown.

Leptospirosis is one of the most widespread diseases estimated to infect up to 7-10 million people per year worldwide (2014) that can be transmitted from animals to humans. The most common transmission is via the urine of rodents or domestic animals that contaminates water or soil. Unfortunately, it can cause severe infection and currently there is not an efficient vaccine present to combat this disease. The disease is caused by Leptospira, a genus of the spirochaete bacteria of which there are ~13 pathogenic species that effect humans. The signs and symptoms of the disease are quite variable and can range from mild headaches, muscle pains, and fevers to the more severe form which causes bleeding from the lungs.

Enteric disease and respiratory diseases are major problems worldwide which greatly impact human health, as well as animal health. Current vaccine approaches are limited by numerous factors, including production costs, efficacy, safety, requirement of adjuvants, and storage conditions. 

Effective adjuvants enhance antigen immunogenicity and/or modulate the type of immunity (e.g., humoral vs. cellular immune response), and, in theory, an optimal antigen-adjuvant combination should activate the both arms of the immune system (innate and adaptive immunity). Different adjuvants work via different mechanisms and, ultimately, the best adjuvant for any specific vaccine will be chosen on the basis of compatibility with the delivery route (e.g., systemic vs. mucosal), ability to provoke the desired immune response (e.g., humoral vs. cellular immunity), and relevance to a particular stage of the required anti-microbial protection (e.g., preventive vs. therapeutic immunity). One way to achieve these diverse goals is to use a combination of complementary, synergistic adjuvants and this is one current practice. However, an adjuvant that could trigger the immunomodulatory cascade upstream of current options could simplify the design of safe and effective vaccines and revolutionize modern day vaccinations.

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As part of a comprehensive campaign to screen for effective vaccine adjuvants, 180,000 compounds were tested in a cell-based HTS screen to assess ability to activate NF-kB. Several classes of scaffolds bearing appropriate substitutions were found to stimulate innate immune responses and some of these scaffolds were structurally different from all other known ligands. More interestingly, the structure of one class of scaffolds challenges current dogma regarding what is necessary for efficacy.

Herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital herpes, a sexually transmitted disease estimated to affect more than 500 million people worldwide. About one in six people in the United States aged between 14 and 49 years has genital herpes caused by HSV-2. In addition to causing painful recurring genital sores and emotional stress in those infected, the disease can be particularly severe in immunosuppressed patients and can cause death or brain damage in babies born to infected mothers. Antiviral drugs are being used widely to treat HSV-2, but they are ineffective at eradicating the disease. There is therefore an urgent need for a safe and effective HSV-2 vaccine.

Group A streptococcus (GAS) is a ubiquitous human pathogen behind a spectrum of diseases. Worldwide, invasive S. pyogenes infections result in excess of half a million deaths each year. To date, there has been no effective GAS vaccine developed in part because there are more than 150 serotypes. A diagnostic for GAS has been developed utilizing the carbohydrate structure of the GAS called Group A carbohydrate (GAC) consisting of a rhamnose backbone and an immunodominant N-acetylglucosamine (GlcNAc) side chain. Initially, utilizing this same structure as a potential vaccine produced good outcomes in animals but safety concerns were raised since antibodies generated against the GlcNAc side chain could precipitate other conditions (e.g. rheumatic carditis and Sydenham's chorea).

While successful vaccines have been developed against acute infections, persistent infections have remained refractory to both natural immunity and vaccination protocols. The standard strategy of selecting immunogens on their ability to generate a strong T-cell response has proven ineffective. In reality, one observes immunogens that generate a surfeit of T-cells but are completely ineffective as vaccines. On the other hand, one can immunize with DNA and get protection using a gene against which no immunity is generated during natural infection. Therefore, to vaccinate against persistent infections, a vaccine may have to be better than natural immunity. An effective approach may be evolved by learning from and targeting the "Achilles heel" of natural immunity.