Cytomegalovirus vaccine
{{Short description|Vaccine to prevent cytomegalovirus (CMV) infection}}
A Cytomegalovirus vaccine is a vaccine to prevent cytomegalovirus (CMV) infection or curb virus re-activation (symptomatic flare-ups) in persons already infected. Challenges in developing a vaccine include adeptness of CMV in evading the immune system and limited animal models.{{cite book | vauthors=Inoue N, Abe M, Kobayashi R, Yamada S| title=Human Herpesviruses | chapter=Vaccine Development for Cytomegalovirus | series=Advances in Experimental Medicine and Biology | volume=1045 | pages=271–296 | year=2018 | doi=10.1007/978-981-10-7230-7_13 | pmid = 29896672 | isbn=978-981-10-7229-1 }} As of 2018 no such vaccine exists, although a number of vaccine candidates are under investigation. They include recombinant protein, live attenuated, DNA and other vaccines.{{Cite journal | doi = 10.1586/ERV.13.46| pmid = 23750795| title = Recent advances in designing an effective vaccine to prevent cytomegalovirus-associated clinical diseases| journal = Expert Review of Vaccines| volume = 12| issue = 6| pages = 661–76| year = 2013| last1 = Dasari | first1 = V. | last2 = Smith | first2 = C. | last3 = Khanna | first3 = R. | s2cid = 7062201}}{{cite journal |vauthors=Zhong J, Rist M, Cooper L, Smith C, Khanna R |title=Induction of pluripotent protective immunity following immunisation with a chimeric vaccine against human cytomegalovirus |journal=PLoS One |volume=3 |issue=9 |pages=e3256 |year=2008 |pmid=18806877 |pmc=2533118 |doi=10.1371/journal.pone.0003256 |bibcode=2008PLoSO...3.3256Z |doi-access=free }}
As a member of the TORCH complex, cytomegalovirus can cause congenital infection, which can lead to neurological problems, vision and hearing loss. Infection/re-activation of CMV in immuno-compromised persons, including organ transplantation recipients, causes significant mortality and morbidity. Additionally, CMV is implicated in the pathogenesis of various chronic conditions including atherosclerosis and coronary artery disease with recent studies indicating a potential link to increased risk of Alzheimer's disease.{{Cite book |last1=Hajjar |first1=David P. |url=https://books.google.com/books?id=0ToGnkORSAMC&pg=PA25 |title=Role of Herpesviruses in Atherogenesis |last2=Schwartz |first2=Stephen M. |date=1999-02-22 |publisher=CRC Press |isbn=9789057023217}} Therefore naturally there has been considerable effort made towards the development of a CMV vaccine, with particular emphasis on protection of pregnant women.{{cite journal |author=Schleiss MR |title=Comparison of vaccine strategies against congenital CMV infection in the guinea pig model |journal=J. Clin. Virol. |volume=41 |issue=3 |pages=224–30 |date=March 2008 |pmid=18060834 |doi=10.1016/j.jcv.2007.10.008 }} Development of such a vaccine has been emphasized as a priority by the National Vaccine Program Office in the United States.{{cite journal |vauthors=Khanna R, Diamond DJ |date=January 2006 |title=Human cytomegalovirus vaccine: time to look for alternative options |journal=Trends Mol Med |volume=12 |issue=1 |pages=26–33 |doi=10.1016/j.molmed.2005.11.006 |pmid=16337831}}{{cite journal |vauthors=Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R |date=July 2004 |title=Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee |journal=Clin. Infect. Dis. |volume=39 |issue=2 |pages=233–9 |doi=10.1086/421999 |pmid=15307033 |doi-access=free}}
Since vaccination of the immunocompromised persons introduces additional challenges, members of this population are less likely to be candidates for such a vaccine.{{cite journal |vauthors=Schleiss MR, Heineman TC |title=Progress toward an elusive goal: current status of cytomegalovirus vaccines |journal=Expert Rev Vaccines |volume=4 |issue=3 |pages=381–406 |date=June 2005 |pmid=16026251 |doi=10.1586/14760584.4.3.381 |s2cid=5100637 }}
Recombinant gB subunit vaccine
A phase 2 study of a recombinant gB protein subunit CMV-vaccine "gB/MF59" was published in 2009 and indicated an efficacy of 50% in seronegative women of childbearing-age thus the protection provided was limited and a number of subjects contracted CMV infection despite the vaccination. In one case congenital CMV was encountered.{{cite journal |vauthors=Pass RF, Zhang C, Evans A, etal | title=Vaccine prevention of maternal cytomegalovirus infection| journal=N Engl J Med |pmid=19297572| year=2009| volume=360| issue=12| pages=1191–9| doi=10.1056/NEJMoa0804749| pmc=2753425}} Another phase 2 study of the same vaccine was done in patients awaiting kidney transplantation. The vaccine significantly boosted the antibody levels and reduced the duration of post-transplantation viremia.
Despite years of investigation into "gB/MF59" important unresolved questions remain. It appears that immunity to one CMV strain does not mean immunity to all strains, to what extent then will "gB/MF59" which is based on the sequence of the ancestrally-African strain "Towne" provide immunity to diverse strains.{{Cite journal |last=Schleiss |first=Mark R. |date=2018-06-12 |title=Recombinant cytomegalovirus glycoprotein B vaccine: Rethinking the immunological basis of protection |url=https://www.pnas.org/doi/10.1073/pnas.1806420115 |journal=Proceedings of the National Academy of Sciences |volume=115 |issue=24 |pages=6110–6112 |doi=10.1073/pnas.1806420115 |pmc=6004476 |pmid=29875141}}{{Cite journal |last=Charles |first=Oscar J. |last2=Venturini |first2=Cristina |last3=Gantt |first3=Soren |last4=Atkinson |first4=Claire |last5=Griffiths |first5=Paul |last6=Goldstein |first6=Richard A. |last7=Breuer |first7=Judith |date=2023-07-25 |title=Genomic and geographical structure of human cytomegalovirus |url=https://www.pnas.org/doi/abs/10.1073/pnas.2221797120 |journal=Proceedings of the National Academy of Sciences |volume=120 |issue=30 |pages=e2221797120 |doi=10.1073/pnas.2221797120 |pmc=10372631 |pmid=37459519}} Furthermore the immunological mechanism underlying gB-vaccine mediated protection is unclear. Initially it was assumed that antiviral immunity was caused via induction of a virus-neutralising antibody response, but followup analyses have disproved this and the true mechanism of protection is currently unclear.
Further research
In 2013, Astellas Pharma has started on individuals who received a hematopoietic stem cell transplant a Phase III trial with its CMV deoxyribonucleic acid DNA cytomegalovirus vaccine ASP0113.{{cite web|url=https://clinicaltrials.gov/ct2/show/NCT01877655 |title=A Study to Evaluate a Therapeutic Vaccine, ASP0113, in Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, Hematopoietic Cell Transplant (HCT) (HELIOS) |publisher=ClinicalTrials.gov |date=2013-06-12 |access-date=2015-10-26}}
In 2015, Astellas Pharma has commenced on healthy volunteers a Phase I trial with its cytomegalovirus vaccine ASP0113.{{cite web|url=https://clinicaltrials.gov/ct2/show/NCT02103426 |title=An Evaluation of a Cytomegalovirus (CMV) Vaccine (ASP0113) in CMV-Seropositive and CMV-Seronegative Healthy Subjects and CMV-Seronegative Dialysis Patients |publisher=ClinicalTrials.gov |date=2015-07-08 |access-date=2015-10-22}}
In 2016, VBI Vaccines commenced a Phase I preventative cytomegalovirus vaccine study (VBI-1501).{{cite web|title=Study to Evaluate Safety, Tolerability, and Immunogenicity of Candidate Human Cytomegalovirus Vaccine in Healthy Adults - Full Text View - ClinicalTrials.gov|url=https://clinicaltrials.gov/ct2/show/NCT02826798|website=clinicaltrials.gov|access-date=18 September 2016}}
Other cytomegalovirus vaccines candidates are the CMV-MVA Triplex vaccine and the CMVpp65-A*0201 peptide vaccine. Both vaccine candidates are sponsored by the City of Hope National Medical Center. As of 2016, the development is in clinical phase 2 trial stage.{{cite web|url=https://clinicaltrials.gov/ct2/show/NCT02506933 |title=Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant |publisher=ClinicalTrials.gov |date=2015-07-21 |access-date=2016-01-23}}{{cite web|url=https://clinicaltrials.gov/ct2/show/NCT02396134 |title=Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant |publisher=ClinicalTrials.gov |date=2015-03-12 |access-date=2016-01-23}}
In March 2019, Helocyte and City of Hope National Medical Center announced positive phase two results for Triplex. They are working on finding funding for Phase III research and then FDA approval.
Moderna is working on mRNA-1647, a mRNA CMV vaccine. It was the first mRNA vaccine to enter phase 2 clinical trials.{{cite web |last1=Lowe |first1=Derek |title=Moderna's Upcoming Clinical Trials |url=https://www.science.org/content/blog-post/moderna-s-upcoming-clinical-trials |website=In the Pipeline |publisher=American Association for the Advancement of Science |access-date=19 October 2021 |date=21 Apr 2021}}