Joining the race to develop a vaccine against the Zika virus (ZIKV), scientists at the University of Pennsylvania School of Medicine and other institutions report that they have developed an investigational vaccine that incorporates messenger RNA (mRNA) and induces a powerfully protective immune response. Thus far, the vaccine has shown promise in mice and monkeys. The animals acquired strong protection after receiving a single dose.
Details of this work appeared February 2 in the journal Nature, in an article entitled, “Zika Virus Protection by a Single Low-Dose Nucleoside-Modified mRNA Vaccination.” The article described how the new candidate vaccine elicited rapid and durable protective immunity without adverse events. This vaccine is the first to show such potent and long-lasting protection without the use of a live virus.
“Here, we demonstrate that a single low-dose intradermal immunization with lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope (prM-E) glycoproteins of a 2013 ZIKV outbreak strain elicited potent and durable neutralizing antibody responses in mice and non-human primates,” wrote the article’s authors. “Immunization with 30 μg of nucleoside-modified ZIKV mRNA-LNPs protected mice from ZIKV challenges at 2 weeks or 5 months post-vaccination, and a single dose of 50 μg was sufficient to protect non-human primates from a challenge at 5 weeks post-vaccination.”
Injected mRNAs normally would be cleared from the body within minutes by a patient's immune system, but these mRNAs are modified so that they are ignored by the immune system and can easily enter cells. Once inside cells, they are taken up by cellular protein-making machinery and induce the production, over weeks, of the viral proteins they encode.
This extended production of viral proteins mimics what a live virus vaccine would achieve. Live virus vaccines—using slow-replicating versions of the virus they are meant to protect against—tend to induce much more powerful immune protection compared to vaccines that are based on nonreplicating versions of a virus or isolated viral proteins. Live virus vaccines have serious potential drawbacks, though, including harmful infection with the virus in people who have weakened immune systems.
Some newer vaccine candidates use harmless viruses, such as modified adenoviruses, to deliver genes that encode immunizing viral proteins. To date, an adenovirus-based strategy is the only Zika vaccine candidate that has shown strong protection in monkeys with a single dose; however, the immune system tends to attack adenoviruses, and in some cases, it may neutralize them before they can deliver their immunizing payloads.
The mRNA-based strategy has none of these drawbacks.
The new candidate vaccine contains mRNAs encoding two key proteins from a Zika virus strain isolated in a 2013 outbreak. The researchers found that in mice, a single injection of 30 millionths of a gram of these mRNAs—a small fraction of the dose used for a typical vaccine—induced a rapid immune response, which protected mice from intravenous exposure to a separate Zika strain 2 weeks later. That protection, resulting in zero detectable virus in the bloodstream a few days after exposure, was maintained even when the mice were exposed to Zika virus 5 months after vaccination.
Tests in macaque monkeys also showed that a single vaccine dose of only 50 μg provided strong protection against exposure to Zika virus 5 weeks later.
In both cases, virus neutralization tests indicated that the vaccine induced high levels of antibodies that block Zika infection—levels that peaked after several weeks and thereafter remained high enough to be protective, potentially for years.
“Our work so far suggests that this new vaccine strategy induces a level of virus neutralization about 25 times greater, after a single dose, than one sees in standard vaccines,” said Drew Weissman, M.D., Ph.D., a professor of infectious disease at Penn and the senior author of the current study.
The powerful, durable protection conferred by the candidate vaccine is due in large part to its strong stimulation of CD4 helper T cells, which are important for maintaining long-term antibody immunity.
The mRNA vaccine approach has other advantages, Dr. Weissman added: “If a vaccine is effective after just a single immunization, the infrastructure needed for its administration can be much simpler. Production of an mRNA-based vaccine is also likely to be easier and less expensive compared to traditional virus- or viral protein-based vaccines.”
Dr. Weissman and colleagues are also applying their mRNA-based strategy to the development of other vaccines and therapies.