Prospects and perspectives for development of a vaccine against herpes simplex virus infections

Abstract

Herpes simplex viruses 1 and 2 are human pathogens that lead to significant morbidity and mortality in certain clinical settings. The development of effective antiviral medications, however, has had little discernible impact on the epidemiology of these pathogens, largely because the majority of infections are clinically silent. Decades of work have gone into various candidate HSV vaccines, but to date none has demonstrated sufficient efficacy to warrant licensure. This review examines developments in HSV immunology and vaccine development published since 2010, and assesses the prospects for improved immunization strategies that may result in an effective, licensed vaccine in the near future.

Keywords::

• cell-mediated immunity
• clinical trials
• glycoprotein
• herpes simplex
• humoral immunity
• latency
• vaccination

Financial & competing interests disclosure

This work was supported by grants R01HD044864, R01HD038416 and K12 HD68322 from the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Antivirals for herpes simplex virus (HSV) infection have not significantly altered the epidemiology of HSV infections; therefore, vaccination is required to reduce morbidity and mortality.

• Significant differences in the natural history of varicella zoster virus infection compared with HSV, particularly the lack of viral protein expression during HSV latency, may inform the development of future candidate HSV vaccines. The short incubation period for HSV as well as the limited viremic stage of primary infection further complicates vaccine development; mucosal immunity may be more important than systemic IgG response.

• Protective adaptive responses in immune-seronegative and asymptomatic subjects seem to be skewed toward early HSV proteins. Future candidate vaccines should include some of these ‘protective’ and ‘asymptomatic’ antigens.

• Antibodies induced by experimental vaccines that are found to have neutralizing activity in vitro may have little or no effect on viral neutralization in vivo, possibly because of inadequate tissue-specific concentrations, pH-dependency of certain antigens and the inherent inability of antibody to prevent cell-to-cell spread of progeny virus during lytic replication.

• Cell-mediated immunity (CMI) is essential for control of HSV infection and may in some instances develop in the absence of a humoral response. However, tools for assessing the effectiveness of CMI responses are infrequently employed in vaccine research and little standardization and consensus opinion on correlates of infection has been established.

• Further development in adjuvant technology may increase our ability to induce innate immune mechanisms, CMI and responses targeted to key mucosal sites.

• Innovative work dissecting and characterizing local resident T-cell populations in individuals with excellent disease control may lead to novel future vaccine approaches.