A Vectored Measles Virus Induces Hepatitis B Surface Antigen Antibodies While Protecting Macaques against Measles Virus Challenge

Abstract

Vaccines based on live viruses can be highly effective and easy to produce and deliver. Smallpox was eradicated with live vaccinia virus, and a live attenuated poliovirus vaccine has been at the core of the polio eradication campaign (17). Worldwide measles virus (MV) vaccination prevents an estimated 80 million cases and 4.5 million deaths annually (45) with minimal severe adverse effects, on average less than 10 in 1 million doses (34). With the currently recommended vaccination scheme, the first dose of vaccine given at 10 to 12 months of age confers long-lasting immunity to 95% of vaccinees (16). The second dose, given to 6-year-olds, raises the conversion rate to nearly 100%, eliminating primary vaccine failures (45). The two-dose strategy has been credited with elimination of indigenous measles in several countries (9), and the live attenuated MV vaccine is considered to be one of the safest and most cost-effective health tools available (28).MV is a nonsegmented negative-strand RNA virus replicating in the cytoplasm. Vaccine safety and efficacy are sustained by lack of recombination, lack of a DNA replication phase, established vaccine production methods, and effective distribution networks (2, 50). A reverse genetic system (37) allows generation of recombinant MV expressing heterologous proteins, including those of other pathogens (48). For this, coding regions are inserted between duplicated MV-specific gene start and gene end motifs that direct transcription by the viral RNAdependent RNA polymerase. These expression cassettes are named additional transcription units (ATUs). The genomic location of an ATU determines the amount of protein expressed due to the sequential attenuation of transcription at gene ends (6,18).Work towards developing recombinant MV with additional vaccine specificities has begun: genes from hepatitis B virus (HBV) (43), simian and human immunodeficiency viruses (24, 52), mumps virus (50), and West Nile virus (10) have been inserted into different positions in the MV genome and thus expressed at different levels. The immunogenicities of vectored MVs and, in one case, their vaccine efficacies have been characterized in rodent and primate animal models. An MV-based candidate vaccine protected interferon (IFN) receptor-deficient mice against West Nile virus challenge (10).The widely used HBV vaccine is based on Saccharomyces cerevisiae-expressed small surface antigen (hepatitis B surface antigen [HBsAg]) and has a three-dose schedule (22). This vaccine provides enduring and protective immunity, but compliance with this regimen is often low, and a long-desired global immunization is not in sight. To facilitate HBV eradication, alternatives have been proposed, including a two-dose scheme (1, 4). Replicating HBsAg-expressing viral vectors have also been generated: vaccinia virus (27, 44)-, varicellazoster virus (20, 42)-, adenovirus (25)-, and MV-based vectors (43) produce HBsAg to high levels and elicit protective antiHBsAg antibodies in animal models.

Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed

“…In current ovarian cancer, glioma, and myeloma clinical trials (38), patients cannot be in contact with unvaccinated infants or severely immunocompromised individuals until lack of shedding is established. Sheddingincompetent oncolytic viruses can be generated after transferring the EpR-inactivating mutations to a vaccine genetic background (39,40). We note that the MV vaccine strain has 1-way epithelial crossing characteristics even if it binds CD46, which is abundantly expressed apically and basolaterally in epithelia (13).…”

Measles Virus Defective Interfering RNAs Are Generated Frequently and Early in the Absence of C Protein and Can Be Destabilized by Adenosine Deaminase Acting on RNA-1-Like Hypermutations

“…DI-RNAs may alter the characteristics of MV live-attenuated vaccines and modulate the efficacy of recombinant MV engineered for vaccination against heterologous pathogens or used as oncolytic vectors (27,(66)(67)(68). While vaccine producers seek to avoid DI-RNAs in order to standardize efficacy, oncolytic potency may not rely uniquely on efficient viral replication and cell lysis but may also rely on immunostimulatory properties (69,70).…”

Live-Attenuated Measles Virus Vaccine Targets Dendritic Cells and Macrophages in Muscle of Nonhuman Primates

“…(33). Similarly, subcutaneous vaccination of macaques with 10 4 infectious units of Moratenbased rMVs found that positions 3 and 6 induced equivalent immune responses for the parameters examined (34). However, another recent study showed that insertion of an ATU into positions 3 and 6 of a human parainfluenza virus 3 vaccine candidate caused a temperature-sensitive phenotype, resulting in attenuation of the virus in vivo (35).…”