mRNA offers a new and promising approach for vaccine development”
Examples of viruses that cause latent infection include herpes simplex virus (HSV), which infects over four billion people worldwide;3 cytomegalovirus (CMV), which is the number one infectious cause of birth defects;4 and Epstein–Barr virus (EBV), a highly prevalent virus that is the main cause of infectious mononucleosis (mono) and other illnesses that can be severe.5 To date, there are no vaccines approved for use against HSV, CMV, EBV or most other latent viral infections. Historically, the approach to developing vaccines against latent viruses has been just as varied as the viruses themselves.
mRNA offers a new and promising approach for vaccine development. While most of the world recognises mRNA as the basis of the vaccines used against a global pandemic over the last two years, I like to think of mRNA as a skeleton key that, when customised in the right way, could be used to address many types of infectious agents. The concept truly inspires when we consider applying mRNA to pathogens like latent viruses, which cause infections that have been thought to occur along distinct pathways and are driven by different viral gene products.6
CMV is an example of a latent virus that is a prime focus for the next potential mRNA vaccine. This virus is a type of herpesvirus, all of which cause an initial active infection and then become latent within specific host cells.7,8 In the latent state, the genome resides in host cells, but no virus particles are generated to cause symptoms or detectable illness.9 However, if initial CMV infection, re-infection or reactivation of latent CMV occurs during pregnancy,8 it may lead to severe sequelae in newborns.10,11
The prevalence of CMV infection generally increases with age12 and is a relatively common infection worldwide, with 83 percent of the global adult population infected.13 In the US, minority populations and households with lower income or education levels are observed to have higher CMV prevalence and younger age of CMV acquisition compared to the general population.14 As a result, black and multiracial infants are almost two times more likely to have congenital CMV infection compared to non-hispanic white infants.15 Due to the staggering burden of CMV and its complications in newborns, it has long been a priority of researchers to develop a vaccine against CMV.16 In fact, the development of a vaccine to prevent CMV infection has been designated as one of the highest priorities by the US National Academy of Medicine for two decades.
While some previous vaccine candidates have shown partial efficacy in CMV, there have been challenges in getting a vaccine candidate to elicit durable, robust humoral and cellular immune responses.17,18 Part of the challenge is the complexity of the virus. Human CMV possesses a large viral genome that is enclosed in a capsid, surrounded by an outer envelope that contains at least 19 proteins.19,20 Recent research has identified two of these envelope proteins as being critical for infection of human cells and elicitation of an immune response, namely glycoprotein B (gB) and the pentamer complex.20 This is where the potential of mRNA technology becomes truly exciting.
mRNA allows for the ability of multiplexing for more compelling vaccine profiles. Multiple mRNAs encoding for multiple viral proteins can be included in a single vaccine, permitting production of complex multimeric antigens that are more difficult to achieve with traditional technologies. mRNA‑1647, being developed by our team at Moderna, is composed of six mRNAs that encode the gB protein and the five components of the pentamer complex. Both the pentamer and gB are essential for CMV to infect barrier epithelial surfaces and gain access to the body, which is the first step in CMV infection. The six mRNAs are packaged in lipid nanoparticles that are a complex assembly of four types of lipids and are designed to stabilise the mRNAs in solution and facilitate mRNA entry into the cell. This is critical for immune response generation after vaccination and protection against future CMV infection.
The prevalence of CMV infection generally increases with age and is a relatively common infection worldwide”
Beyond an mRNA-based vaccine, there is a limited number of other candidates for CMV that are currently being tested in advanced clinical studies and each study takes a different approach to tackling the virus. One example is a vaccine candidate based on recombinant gB and pentamer antigens combined with an adjuvant21 which has begun a Phase I/II study (NCT05089630). Others focus more specifically on immunosuppressed populations at high risk for CMV complications such as HIV-infected patients or those undergoing transplantation.
The range of approaches being taken to halt CMV transmission is reflective of the virus’ proliferation, as it impacts so many different groups of people. The two main groups at highest risk for complications following CMV infection are unborn children and people with compromised immune systems.22
The range of approaches being taken to halt CMV transmission is reflective of the virus’ proliferation”
The first group at risk for devastating effects of CMV infection are unborn children who acquire CMV when an infected pregnant mother passes the virus across the placenta to her unborn child. CMV is the most common congenital infection worldwide; approximately one percent of babies born in developed countries and up to six percent of babies born in developing countries have congenital CMV infection.23,24 In the US, this equates to about 40,000 infants born each year with congenital CMV infection. About 20 percent of babies born with congenital CMV infection will experience long-term effects including hearing loss, vision impairment, cognitive impairment and decreased muscle strength and co-ordination.23,25
The second group at high risk for CMV complications are people with compromised immune systems, such as transplant recipients and those with HIV infection.11,23 CMV complications in these populations most often occurs from reactivation of a latent CMV infection that occurs due to the drug-induced immune suppression that occurs in transplant patients or due to immune suppression caused by HIV infection. The resulting uncontrolled CMV replication increases the risk of transplant failure, CMV-related organ failure and even death.8,26
Manufacturing mRNA is also uniquely efficient compared to traditional vaccine development”
If an mRNA vaccine proves to be safe and effective in preventing initial CMV infection, an equally important task is to assess whether a CMV vaccine can help provide defence when latent CMV reactivates or when a new CMV strain infects previously infected individuals. Globally, more than two-thirds of infants with congenital CMV infection are estimated to be born to mothers who were infected prior to pregnancy.25 We aim to explore the effect of our CMV vaccine candidate in seropositive populations during the course of its clinical development.
However, CMV is just one focal point. An mRNA‑based vaccine approach to other latent viruses including HSV or EBV has the potential to overcome some long-standing historical challenges.
The key advantage of mRNA-based vaccines is that they can be tailored to closely mimic the key antigens produced during a natural viral infection. This ‘educates’ the immune system to effectively prevent infection if it comes into contact with the actual virus. This can potentially enhance the immune response, including improved B- and T-cell responses for latent viral infections.
Manufacturing mRNA is also uniquely efficient compared to traditional vaccine development. Traditional vaccine manufacturing has required dedicated production processes, facilities and operators that are specific for each vaccine, which can result in added operational costs and delayed availability of vaccines. However, mRNA vaccines are produced in a consistent manufacturing process that allows the use of a single facility to produce many different vaccines. This shared manufacturing process and infrastructure is vital for successful global vaccination.
It is advantageous that we, as researchers, re‑evaluate the methodology in which we efficiently develop safe and effective modern-day vaccines for latent viruses that have been allowed to hide among us for so long.
About the Author
Dr Sandeep Basnet is Director of Clinical Development, Infectious Diseases at Moderna and is one of the clinical leads in the CMV vaccine development programme. Prior to joining Moderna, he was an Associate Director in a rare disease clinical development programme at Alexion Pharmaceuticals, Boston, US.
- Speck SH, Ganem D. Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe [Internet]. 2010;8(1):100–15. http://dx.doi.org/10.1016/j.chom.2010.06.014
- Viral latency [Internet]. Hiv.gov. [cited 2022 Mar 7]. Available from: https://clinicalinfo.hiv.gov/en/glossary/viral-latency
- Herpes simplex virus [Internet]. Who.int. [cited 2022 Mar 7]. Available from: https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus
- Congenital CMV and hearing loss [Internet]. Cdc.gov. 2021 [cited 2022 Mar 7]. Available from: https://www.cdc.gov/cmv/hearing-loss.html
- About Epstein-Barr virus (EBV) [Internet].
Cdc.gov. 2021 [cited 2022 Mar 7]. Available from: https://www.cdc.gov/epstein-barr/about-ebv.html
- Raja P, Lee JS, Pan D, Pesola JM, et al. A herpesviral lytic protein regulates the structure of latent viral chromatin. MBio [Internet]. 2016;7(3). http://dx.doi.org/10.1128/mBio.00633-16
- Whitley R. Herpesviruses. In: Medical Microbiology. NCBI Bookshelf.
- La Rosa C and Diamond D. The immune response to human CMV. Future Virol. 2012 March 1; 7(3): 279–293. doi:10.2217/fvl.12.8.
- Forte E, Zhang Z, Thorp EB and Hummel M. Cytomegalovirus Latency and Reactivation:
An Intricate Interplay With the Host Immune Response. Front. Cell. Infect. Microbiol. 2020 March; 10:130. doi: 10.3389/fcimb.2020.00130
- Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical outcome. Clin Infect Dis [Internet]. 2013;57 Suppl 4(suppl 4):S178-81. http://dx.doi.org/10.1093/cid/cit629
- Griffiths P, Baraniak I, Reeves M. The pathogenesis of human cytomegalovirus: Pathogenesis of human cytomegalovirus. J Pathol [Internet]. 2015;235(2):288–97. http://dx.doi.org/10.1002/path.4437
- Michael J. Cannon DSSATBH. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection [Internet]. Wiley InterScience. 2010 June 18; 20: 202–213.
- Zuhair M, Smit GSA, Wallis G, et al. Estimation of the worldwide seroprevalence of cytomegalovirus:
A systematic review and meta‐analysis. Rev Med Virol. 2019; e2034. https://doi.org/10.1002/rmv.2034
- Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis [Internet]. 2010;50(11):1439–47.
- Fowler KB, Ross SA, Shimamura M, Ahmed A, et al. Racial and ethnic differences in the prevalence of congenital Cytomegalovirus infection. J Pediatr [Internet]. 2018;200:196-201.e1. http://dx.doi.org/10.1016/j.jpeds.2018.04.043
- Institute of Medicine (US) Committee to Study Priorities for Vaccine Development; Stratton KR, Durch JS, Lawrence RS, editors. Vaccines for the
21st Century: A Tool for Decisionmaking.
Washington (DC): National Academies Press (US); 2000. https://www.ncbi.nlm.nih.gov/books/NBK233313/ doi: 10.17226/5501
- Diamond D, La Rosa C, Chiuppesi F, Contreras H, et al. (2018): A fifty-year odyssey: Prospects for a cytomegalovirus vaccine in transplant and congenital infection, Expert Review of Vaccines, DOI: 10.1080/14760584.2018.1526085
- Fu T-M, An Z, Wang D. Progress on pursuit of human cytomegalovirus vaccines for prevention of congenital infection and disease. Vaccine [Internet]. 2014;32(22):2525–33. http://dx.doi.org/10.1016/j.vaccine.2014.03.057
- Gibson W. Structure and formation of the cytomegalovirus virion. Curr Top Microbiol Immunol [Internet]. 2008;325:187–204. http://dx.doi.org/10.1007/978-3-540-77349-8_11
- Foglierini M, Marcandalli J, Perez L. HCMV envelope glycoprotein diversity demystified. Front Microbiol [Internet]. 2019;10:1005. http://dx.doi.org/10.3389/fmicb.2019.01005
- Plotkin SA, Wang D, Oualim A, Diamond DJ, et al. The status of vaccine development against the human Cytomegalovirus. J Infect Dis [Internet]. 2020;221(Suppl 1):S113–22. http://dx.doi.org/10.1093/infdis/jiz447
- CMV [Internet]. Cdc.gov. 2021 [cited 2022 Mar 7]. https://www.cdc.gov/cmv/clinical/overview.html
- Cheeran MC-J, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev [Internet]. 2009;22(1):99–126, Table of Contents. http://dx.doi.org/10.1128/CMR.00023-08
- T.M. Lanzieri et al. / International Journal of Infectious Diseases 22 (2014) 44–48
- Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev [Internet]. 2013;26(1):86–102. http://dx.doi.org/10.1128/CMR.00062-12
- Husain S, Pietrangeli CE, Zeevi A. Delayed onset CMV disease in solid organ transplant recipients. Transpl Immunol [Internet]. 2009;21(1):1–9.