mRNA technology may hold the future for a cytomegalovirus vaccine

Listen to this article on the DDW podcast: Allison August, M.D., Vice President, Clinical Development, Infectious Diseases at Moderna examines the data on cytomegalovirus (CMV), why attempts at vaccines for CMV have so far proved elusive and the emerging options to address this unmet need. Although cytomegalovirus (CMV) is almost ubiquitous in the adult population globally, it is an under-recognised infectious cause of birth defects with potentially severe neurological consequences. While there are steps that individuals can take to reduce their risk of contracting CMV, there are no existing treatments or preventative vaccines to address CMV transmission, the subsequent infection or the longer-term manifestations of infection. Here, we delve into the data on CMV, including why previous attempts at vaccines for CMV have proved elusive and the emerging options to address a vast unmet need. What is cytomegalovirus? CMV is a member of the herpesvirus family, which also includes viruses such as the varicella-zoster virus, which causes the chickenpox and the Epstein-Barr virus1. People of all ages worldwide can be infected with CMV2,3. In developed countries, nearly one in three children are infected with CMV by the age of five, and in developing countries, the infection rate in children is even higher3,4. Even though an infected child can seem healthy and may not appear to have any symptoms of illness, it is possible for them to shed the virus for three to six months or longer. In the United States alone, over half of all adults have been infected with CMV by the age of 40. CMV is transmitted by direct contact with infected body fluids such as saliva, urine, blood, tears, semen or breast milk5. The initial CMV infection causes cold or flu-like symptoms in up to 10% of healthy young adults6. After the initial infection, CMV becomes latent, with the genome residing in cells but no virus particles generated to cause detectable damage or illness7,8. Latent CMV may reactivate occasionally, leading to infection, which is often asymptomatic in individuals with healthy immune systems though still transmissible to others7. While the vast majority of adults do not notice any symptoms when they are infected, CMV can be passed from a pregnant woman to her developing baby, causing congenital CMV infection. Globally, approximately one in 200 infants are born each year with congenital CMV infection. Of those cases, approximately 20% result in long-term consequences and even, in some cases, death9,3. Congenital CMV is the number one infectious cause of birth defects, including hearing loss or cognitive impairment, in the United States9. In addition to newborns, CMV can result in serious consequences for people with compromised immune systems, including those with organ or bone marrow transplants, or those with advanced human immunodeficiency virus (HIV)10. The knowledge gap Most of the general public and many healthcare providers in the United States are unaware of the virus itself and its potentially devastating consequences. A recent Harris Poll conducted by Moderna in the United States of 5,000 adults of reproductive age showed that only about 21% of people aged 18 to 40 years have ever heard of CMV, ranking it as one of the least well-known contagious infections among this population. Only about 1 in 10 adults knew basic facts about the disease, including means of transmission and consequences of acquiring CMV infection at birth. Of all healthcare providers surveyed in the poll (n600), 43% could correctly answer that CMV is the leading cause of birth defects in the United States; rates were lowest for primary care providers (32%) and highest for paediatricians (77%). Most of this low awareness is likely attributed to the fact there is currently a lack of vaccines or treatments for CMV that healthcare providers can offer. Progression of vaccines Over two decades ago, the National Academy of Medicine declared the development of a vaccine to prevent congenital CMV infection one of the highest public health priorities11. It determined that a vaccine for CMV would not only improve the quality of life overall in the population but would also be cost saving to the economy. Any vaccine that confers protection against primary CMV infection in women of reproductive age would in theory reduce the risk of congenital CMV transmission overall, and the subsequent potential for developing serious health conditions. In fact, this is exactly what has occurred for rubella in the Americas. Rubella is very contagious and can be dangerous for a pregnant woman and her developing foetus12. Prior to the development of a vaccine, the rubella virus could cause congenital rubella syndrome in the newborn, which resulted in birth defects such as vision loss, hearing loss and congenital heart defects. In the United States alone, during the last major rubella outbreak before vaccines were available, approximately 20,000 infants were born with congenital rubella syndrome13. In 2015, after a 15-year effort to vaccinate against rubella virus (which is usually administered at the same time with vaccines against measles and mumps), the Americas were declared free of endemic transmission of rubella13. Despite CMV remaining a growing and significant public health threat, there have been some challenges to the development of a vaccine for the prevention of CMV14,15. Efforts to develop a vaccine for CMV have been underway since the 1970s, with at least 17 previous vaccine candidates16,15. While some of these earlier vaccine candidates have shown partial efficacy, the development of a CMV that elicits a durable, robust humoral and cellular immune response has not been achieved14,15. In past trials, live attenuated virus candidates were safe and well-tolerated, but elicited lower vaccine-induced immune responses than what was seen by a non-attenuated virus and did not prevent CMV infection. Recombinant CMV vaccines used a modified version of a CMV protein and showed partial efficacy in preventing CMV infection but did not elicit the production of neutralising antibodies. Part of the challenge in developing a safe and effective vaccine for CMV is linked to the complexity of the CMV virus itself. Human CMV contains a large viral genome enclosed in a capsid, which is surrounded by an outer envelope that contains at least 19 proteins17,18. Two of these proteins, glycoprotein B or gB, and the pentamer complex, are thought to be important in the CMV infection of human cells. Therefore, a vaccine that stimulates an immune response to these proteins is thought likely to be key to conferring a protective immune response against CMV. The potential future of mRNA in CMV prevention An mRNA based vaccine approach to complex viruses such as CMV has the potential to overcome some of the challenges identified in earlier vaccine development efforts. mRNA-based vaccines can be tailored to closely mimic the native state of the key antigens produced during a natural viral infection. When presented with the near-native proteins encoded by an mRNA-based vaccine, the immune system should be primed effectively to prevent infection once exposed to the actual CMV virus. In addition, multiple mRNAs encoding for multiple viral proteins can be included in a single vaccine, permitting successful production of complex multimeric antigens that are more difficult to achieve with traditional technologies. To that end, Moderna is applying its mRNA technology, best known in its vaccine for Covid-19, to develop vaccines for other viruses, including CMV. The company’s CMV investigational vaccine, mRNA-1647, is in its Phase III registration study, known as CMVictory. mRNA-1647 contains six mRNAs in a single vaccine: five mRNAs encode the subunits that form the membrane-bound pentamer complex and one mRNA encodes the full-length membrane-bound glycoprotein B (gB). The investigational mRNA-1647 vaccine is packaged in lipid nanoparticles, or LNPs, that are a complex assembly of four types of lipids; each LNP contains multiple mRNA molecules19. The LNPs are intended to stabilise the mRNA in solution and facilitate mRNA entry into the cell19. Moderna is currently studying mRNA-1647’s effect on the adaptive immune response and its ability to product neutralising antibodies against both the pentamer complex and gB protein for the prevention of CMV infection. Moderna’s CMVictory study is evaluating the safety and efficacy of mRNA-1647 against primary CMV infection in women ages 16-40 years. This study will examine the rate of first CMV infection (seroconversion) in women who receive mRNA-1647 versus those who receive placebo. Moderna is expecting to enroll up to 6,900 women of child-bearing age, at approximately 150 sites globally, starting in the United States, with a goal of 42% of the participants enrolled being persons of colour. CMVictory follows a robust Phase I and Phase II research program that demonstrated the ability for mRNA-1647 to induce functional antibodies against CMV with an acceptable safety profile. While there are currently no treatments or vaccines available, precautions can be taken to prevent CMV transmission, including washing hands and not sharing utensils and toothbrushes20,11. The development of mRNA-based vaccines may advance the options to tackle latent viruses, including CMV, to thwart their transmission and infectious consequences. Volume 23 – Issue 4, Fall 2022 About the author Allison August is a board-certified Obstetrician Gynaecologist with over 20 years of maternal health experience. Dr August serves as the Vice President of Clinical Development and Infectious Diseases at Moderna, where her team is studying a potential cytomegalovirus (CMV) vaccine (mRNA-1647). References Whitley RJ. Herpesviruses. In: Baron S, editor. Medical Microbiology. 4th ed. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 68. PMID: 21413307. Zuhair M, Smit GSA, Wallis G, et al. 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Progress on pursuit of human cytomegalovirus vaccines for prevention of congenital infection and disease. Vaccine, 32(22), 2525-2533. Elek SD, Stern H. Development of a vaccine against mental retardation caused by cytomegalovirus infection in utero. Lancet. 1974 Jan 5;1(7845):1-5. doi: 10.1016/s0140-6736(74)92997-3. PMID: 4128996. Gibson, W. (2008). Structure and formation of the cytomegalovirus virion. Human cytomegalovirus, 187-204. Foglierini, M., Marcandalli, J., & Perez, L. (2019). HCMV envelope glycoprotein diversity demystified. Frontiers in microbiology, 10, 1005. Hassett, K. J., Benenato, K. E., Jacquinet, E., Lee, A., Woods, A., Yuzhakov, O., ... & Brito, L. A. (2019). Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Molecular Therapy-Nucleic Acids, 15, 1-11. Prevention tips. CMV Prevention and Healthy Pregnancy Tips | National CMV Foundation | National CMV Foundation. (n.d.). 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