mRNA Vaccine Momentum

Before December 2020, when the FDA authorized the use of two COVID-19 messenger RNA (mRNA) vaccines developed by Pfizer and Moderna, the science behind mRNA vaccines had been researched for over 30 years. After the success of the two pioneering COVID-19 vaccines, these companies have been investigating the mRNA technology for its potential use in vaccines against other infections. These include seasonal influenza (flu), cytomegalovirus (CMV), Zika virus, genital herpes and HIV.

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What makes mRNA vaccines different?

mRNA vaccines differ from other types of vaccines in their mechanism of action. Non-mRNA vaccines typically contain attenuated virus, inactivated virus or part of the virus they are formulated to protect against. Upon encountering the benign viral element in these vaccines, the immune system mounts a response and develops memory cells that will fight off the actual virus if it infects the person in the future.

mRNA vaccines do not contain viruses or any part of them. Instead, they deliver mRNA that instructs the cells to make certain proteins that may be present in the virus of concern and those proteins serve as the antigens that activate the immune system. For example, mRNA COVID-19 vaccines carry instructions to make the spike protein sprouting from the surface of the SARS-CoV-2 virus that causes COVID-19.

Because producing mRNA-based vaccines does not require growing viruses, they can typically be manufactured more rapidly than attenuated or inactivated vaccines. They are also relatively easy to modify, so manufacturers can quickly adjust the mRNA vaccine to match the pathogens in circulation.

mRNA vaccines for seasonal influenza

Current flu vaccines have an efficacy rate of approximately 40% to 60% when circulating strains are well matched to those in the vaccines. Several biopharmaceutical companies are aiming to improve those numbers with mRNA flu vaccines. Moderna and Pfizer both have candidates in late stages of development.

Moderna reported positive phase 3 trial results for its seasonal flu vaccine candidate mRNA-1010. The trial, which enrolled 6,102 participants, compared antibody titer levels and side effects versus Fluarix Quadrivalent, the inactivated seasonal flu vaccine marketed by GSK.

When stacked against Fluarix, Moderna’s mRNA candidate demonstrated higher titer levels and seroconversion rates for A and B flu strains, including A/H1N1, A/H3N2, B/Yamagata and B/Victoria. Similar results were seen in a separate phase 1/2 study comparing mRNA-1010 with Sanofi Pasteur’s Fluzone High-Dose Quadrivalent, a flu vaccine indicated for use in adults 65 years or older.

The investigational vaccine showed an acceptable safety and tolerability profile, raising no safety concerns from data and safety monitoring boards.

Based on these positive results, Moderna plans to meet with regulators and hopes to launch the vaccine in time for the 2024-2025 Northern Hemisphere flu season.

As for Pfizer, the company has enrolled 46,180 adults in a phase 3 study evaluating the safety, efficacy, tolerability and immunogenicity of its modified RNA quadrivalent flu vaccine candidate modFlu. Primary end points include the incidence of laboratory-confirmed flu cases, antibody titer levels and adverse reactions compared with a standard licensed quadrivalent inactivated flu vaccine.

The vaccine candidate met all primary end points during primary analysis, demonstrating superiority to the comparator vaccine and maintaining efficacy through the 2022-2023 flu season. The company expects to complete the trial in March 2024.

Moderna and Pfizer are also developing combination flu and COVID-19 mRNA vaccines. Moderna’s combination candidate is currently in phase 3 trials, whereas Pfizer’s is in phase 2 studies.

mRNA vaccine for cytomegalovirus

CMV is a common virus that causes few to no symptoms in healthy individuals but may lead to serious complications involving the eyes, liver, lungs and other organs in patients who are immunocompromised. Furthermore, CMV can be passed from an infected woman to an infant during pregnancy or childbirth and through breast milk. Congenital CMV infection can lead to hearing loss and other serious sequelae in the infant. Currently, there is no vaccine available to protect against CMV infection.

Once again leveraging the mRNA technology from its COVID-19 vaccine, Moderna is developing a CMV vaccine candidate targeted for females aged 16 to 40 years. The goal is to prevent congenital CMV infection by protecting females of childbearing age.

The investigational vaccine, named mRNA-1647, contains six mRNA sequences encoding glycoprotein B and a pentameric glycoprotein complex, both of which are significant CMV antigens.

The candidate is currently in a phase 3 trial enrolling 6,900 females aged 16 to 40 years. Primary outcomes include antigen-specific seroconversion and adverse events. Trial completion is expected in April 2026.

mRNA vaccine for Zika virus

The Zika virus is another pathogen that can lead to congenital defects, stillbirths or miscarriage if contracted during pregnancy. As with CMV, there are no approved vaccines for Zika virus infection.

Moderna’s mRNA-1893 is an mRNA vaccine candidate currently in a phase 2 trial investigating the safety, tolerability and reactogenicity of a two-dose regimen of the investigational vaccine. The study’s researchers randomly assigned 809 participants aged 18 to 65 years to receive the study vaccine or placebo. Primary outcomes include antigen-specific neutralizing antibodies and adverse events. The study’s estimated completion date is in July 2024.

mRNA vaccines for genital herpes

Herpes simplex virus type 2 (HSV-2) is the leading cause of genital herpes. After primary infection, the virus lies dormant in nerve cells. Periodic reactivation often results in painful lesions in the genital or other mucosal areas.

Moderna and BioNTech are using mRNA technology to develop vaccines to prevent genital herpes lesions in adults infected with HSV-2.

Moderna’s candidate, mRNA-1608, is in a phase 1/2 trial, and BioNTech’s candidate, BNT163, is in a phase 1 study. Both trials have estimated completion dates in June 2025.

mRNA vaccines for HIV

HIV, the virus that causes AIDS, was first identified in 1984. After 40 years and numerous attempts to develop a vaccine, an effective vaccine against the virus does not exist. HIV/AIDS prevention strategies currently rely on fast and effective treatment with antiviral or preexposure prophylaxis with some of the same drugs.

Moderna, in partnership with the National Institute of Allergy and Infectious Diseases, is evaluating the mRNA HIV vaccine candidate mRNA-1574 in the phase 1 HVTN 302 trial. The company has also partnered with the International AIDS Vaccine Initiative (IAVI) in the development of another potential mRNA HIV vaccine,which is a phase 1 trial sponsored by the Bill & Melinda Gates Foundation.

Both trials are enrolling HIV-negative adults. Study locations for the HVTN 302 trial are only in the United States. The other trial’s locations include sites in the United States, Rwanda and South Africa.

Rosanna Sutherby, Pharm.D., is an independent medical writer and community pharmacist in High Point, North Carolina.