Single dose, dual antigen RNA vaccines protect against lethal Crimean-Congo haemorrhagic fever virus infection in mice.

BACKGROUND: Crimean-Congo Haemorrhagic Fever Virus is a tick-borne bunyavirus prevalent across Asia, Africa, the Middle East, and Europe. The virus causes a non-specific febrile illness which may develop into severe haemorrhagic disease. To date, there are no widely approved therapeutics. Recently, we reported an alphavirus-based replicon RNA vaccine which expresses the CCHFV nucleoprotein (repNP) or glycoprotein precursor (repGPC) and is protective against lethal disease in mice. METHODS: Here, we evaluated engineered GPC constructs to find the minimal enhancing epitope of repGPC and test two RNA vaccine approaches to express multiple antigens in vivo to optimize protective efficacy of our repRNA. FINDINGS: Vaccination with repNP and a construct expressing just the Gc antigen (repGc-FL) resulted in equivalent immunogenicity and protective efficacy compared to original repNP + repGPC vaccination. This vaccine was protective when prepared in either of two vaccine approaches, a mixed synthesis reaction producing two RNAs in a single tube and a single RNA expressing two antigens. INTERPRETATION: Overall, our data illustrate two vaccine approaches to deliver two antigens in a single immunization. Both approaches induced protective immune responses against CCHFV in this model. These approaches support their continued development for this and future vaccine candidates for CCHFV and other vaccines where inclusion of multiple antigens would be optimal. FUNDING: This work was supported by the Intramural Research Program, NIAID/NIH, HDT Bio and MCDC Grant #MCDC2204-011.

Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection.

Crimean-Congo hemorrhagic fever virus (CCHFV) causes Crimean-Congo hemorrhagic fever (CCHF) in humans with high morbidity and mortality. Currently, there is neither an approved antiviral drug nor a vaccine against CCHFV. In this study, we describe a lethal model of CCHFV infection using a mouse-adapted strain of CCHFV (MA-CCHFV) in adult wild-type male mice. Infected mice developed high viral loads, tissue pathology, and inflammatory immune responses before ultimately succumbing to the infection. We used the model to evaluate the protective efficacy of nucleoside analogs monulpiravir, favipiravir, ribavirin, the antibiotic tigecycline and the corticosteroids dexamethasone and methylprednisolone against lethal CCHFV infection. Tigecycline, monulpiravir and the corticosteroids failed to protect mice from lethal MA-CCHFV infection. In contrast, favipiravir and ribavirin protected animals from clinical disease and death even when treatment was delayed. Despite demonstrating uniform protection, CCHFV RNA persisted in survivors treated with favipiravir and ribavirin. Nevertheless, the study demonstrated the anti-CCHFV efficacy of favipiravir and ribavirin in a model with intact innate immunity and establishes this model for continued development of CCHFV countermeasures.

Impact of infection or vaccination on pre-existing serological memory.

Once established, serum antibody responses against a specific pathogen may last a lifetime. We describe a cohort of four subjects who received smallpox vaccination, and a single subject who received multiple vaccinations, with antibody levels to unrelated antigens monitored for 1-3 years. These immunizations provided the opportunity to determine if infection/vaccination and the resulting toll-like receptor stimulation would alter antigen-specific serological memory to other antigens, including bacterial toxins (tetanus, diphtheria, and pertussis) and viruses (yellow fever virus, measles, mumps, rubella, Epstein-Barr virus, and varicella-zoster virus). Our results indicate that serum IgG levels are remarkably stable and infection or vaccination are unlikely to increase or decrease pre-existing antigen-specific antibody responses.

Does a clerkship in psychiatry contribute to changing medical students' attitudes towards psychiatry?

OBJECTIVE: The psychiatric clerkship is perceived as an intervention point in medical students' attitude toward psychiatry and career choice after graduation. The authors aim to assess the impact of the psychiatric clerkship in students from Israeli and U.S. origin on their attitude toward psychiatry. METHODS: A modified Nielsen's questionnaire was administered at the start and end of the clerkship in two groups of students. RESULTS: There was no statistically significant difference in attitude scores between the start and endpoint of a clerkship on both the Israeli and the United States groups. Item analysis did not reveal significant impact of clerkship. CONCLUSION: The psychiatry clerkship does not change students' view on the attitude assessed in this study, regardless of their origin (Israeli or U.S.). Further research is needed in order to find more clerkship-dependent contributors to positive or negative attitudes toward psychiatry.

Immune status to poliovirus among immigrant workers in Israel.

BACKGROUND: An essential part of the progress towards the global eradication of poliomyelitis is the ongoing evaluation of populations immunity. Migration of unregistered individuals poses a challenge to such estimations. Moreover, partially immunized immigrants might enlarge immunity gaps and facilitate polio outbreaks in their destination countries. OBJECTIVES: To study the level of immunity to polio in adult foreign workers in Israel. METHODS: Foreign workers (n = 145) from the Philippines, India, and Western Africa were tested for neutralizing antibodies against three IPV strains and an outbreak-associated wild virus. Demographic and immunization data were collected by questionnaires. RESULTS: Seropositivity rates and geometric mean titers (GMTs) for the Mahoney (type 1), MEF (type 2), and Saukett (type 3) poliovirus strains and the wild poliovirus type 1 strain were 99.3% (GMT--233.8), 98.6% (GMT--268.5), 99.3% (GMT--89.4), and 99.3% (GMT--139.5), respectively. Higher GMTs were associated with parenthood and older age. African individuals had significantly higher GMTs for the Saukett strain, compared with individuals from the Philippines and India. CONCLUSIONS: Our results indicate a high level of immunity among foreign workers. More serosurveys are indicated in the future in order to monitor the level of immunity in residents in Israel.