Immune Responses to Herpes Simplex Virus Infection: Implications for Vaccine Development 

(See the Major Article by Mahant et al, on pages 1489–98.)

Genital herpes infections are associated with morbidity, transmission to the neonate, and enhanced transmission of human immunodeficiency virus-1 (HIV-1) [1–3]. Development of effective strategies to interrupt transmission and decrease prevalence in adults will require an understanding of disease transmission and natural history, as well as an understanding of immune responses associated with reduced risk of transmission and acquisition of herpes simplex virus (HSV) infection. Critical insights regarding disease transmission and natural history include recognition that (1) most infections are transmitted during asymptomatic viral shedding or from unrecognized lesions; (2) most transmission occurs from persons who are unaware that they have genital herpes; (3) rates of subclinical shedding of HSV-2 are similar in seropositive persons with and without a history of genital herpes; (4) rates of clinical recurrences are most frequent in the first year following initial genital herpes infection; (5) women, particularly those without prior HSV-1 or HSV-2 infection, have the highest risk of acquisition; and (6) prior HSV-1 infection reduces the severity of first-episode genital HSV-2 infection [1, 4–7]. Finally, the proportion of first episode genital infections caused by HSV-1 has increased in young adults in developed countries, and genital HSV-1 infection results in less frequent symptomatic genital recurrences when compared to recurrent genital HSV-2 infection [8, 9].

Potential strategies for interruption of transmission include education, barrier contraception, vaccination to prevent acquisition of HSV infection, and administration of antiviral therapy or therapeutic vaccines to reduce recurrences and asymptomatic shedding in discordant couples. Short of implementation of widespread antibody screening to identify the roughly 80% of infected individuals with unrecognized HSV-1 and HSV-2 infections, the potential impact of education is largely limited to the 20% who are aware they are infected. Barrier contraception is effective, albeit not as effective as it is in other sexually transmitted diseases such as HIV, gonorrhea, and chlamydia [10]. Daily administration of antiviral medications in persons with recurrent genital herpes decreases lesions, asymptomatic shedding, and transmission to an uninfected partner [11–13]; however, this approach is limited by the cost and inconvenience of daily therapy and will likely have limited overall impact on incidence and prevalence in an infection that is largely transmitted by persons who do not realize that they have genital HSV.

Development of an effective prophylactic vaccine would have the potential advantage of targeted administration to adolescents prior to onset of sexual activity, and a therapeutic vaccine that reduced recurrent episodes and asymptomatic shedding would be more convenient than daily antiviral therapy in persons with established infection even if repeated vaccination was required. As noted in the article by Mahant et al in this issue of The Journal of Infectious Diseases, prophylactic vaccine development has largely focused on development of candidate vaccines that produce neutralizing antibody titers and provide protection in animal models [14]. However, the efficacy shown for these vaccines in clinical trials has been inconsistent, and none have been licensed [15–18].

Of interest is the observation that a glycoprotein D2 vaccine with AS04 adjuvant provided protection from acquisition of HSV-2 in HSV-1/2 seronegative women from male partners with HSV-2 infection but failed in a larger trial in HSV-1/2 seronegative women where efficacy was demonstrated for HSV-1 but not HSV-2 [17, 18]. Sandgren et al have suggested that the protection seen in the former study, which was conducted in couples in established relationships, could have resulted in part from priming following repeated exposure to HSV-2 [19]. There was no requirement for known genital HSV infection in male partners in the latter study, so it is reasonable to assume that exposure to HSV-2 resulting in priming would have been less likely. Another factor in the latter study may be the concurrent increase in first-episode genital HSV-1 infections in the developed countries where the latter trial was conducted.

What is needed is a better understanding of the immunological requirements for protective responses, including different functional activities of antibodies. The most frequently measured functional aspect of antibodies is neutralization, which occurs when antibodies bind pathogen surface antigens and block cellular attachment or entry. Neutralizing titers have often correlated with protective efficacy of vaccines and can be used to benchmark vaccine functionality. Indeed, neutralizing antibodies have in some studies been linked to protective responses against HSV (reviewed in [20]). However, other aspects of antibody function are often overlooked, but can have important roles in protective immune responses.

Antibody dependent cell-mediated cytotoxicity (ADCC) is the process by which antibodies bind to pathogen-encoded antigens on the surface of host cells and recruit effector immune cells (via antibody constant region binding to Fc receptors on effector cells) to target and destroy the infected cell. Similarly, antibodies can recruit complement to lyse infected cells (via complement-dependent cytotoxicity [CDC]) or can opsonize pathogens or infected cells for phagocytosis (via antibody-mediated cellular phagocytosis). These pathways can occur in addition to, or instead of, neutralizing activity.

The subunit HSV-2 gD/AS04 vaccine studied in the Mahant et al article [14], which combines the glycoprotein D with the AS04 adjuvant, was not robustly protective in human clinical trials [17, 18]. Previous studies demonstrated that the vaccine induces neutralizing antibody responses in mice but is not effective in generating antibodies with ADCC function. Mouse studies have shown that an HSV-2 single-cycle virus vaccine lacking gD (ΔgD-2) is more protective against lethal infection than the gD/AS04 vaccine. This increased protection was associated with elevated ADCC and CDC activity [21–23]. A potential mechanism for the lack of gD/AS04-induced ADCC was that gD itself can block induction of a cellular immunomodulatory pathway that is involved in generation of ADCC responses [24]. Therefore, the gD-based vaccines may have an innate ability to block ADCC responses, although this needs to be studied further. More importantly, in a previous neonatal human study, after accounting for neutralizing titers, increased ADCC levels correlated with prevention of disseminated HSV disease [25]. Correlation of ADCC in protecting neonates from HSV-1 and HSV-2 infection was also demonstrated in a mouse model [26]. Therefore, induction of ADCC and potentially CDC, as opposed to neutralizing antibody titers, may be required for successful vaccination against HSV-2.

The study reported by Mahant et al in this issue found that gD/AS04 vaccination in humans induced neutralizing, but not ADCC or CDC, antibodies, while acute infection induced all 3 (with lower neutralizing responses than vaccinated individuals) [14]. ADCC was increased in chronic versus acute HSV-2 patients, and chronic infection was associated with an increased number of antigens targeted by antibodies. These data support the previous mouse studies showing a lack of correlation of neutralizing antibodies with protective responses and suggest that other antibody functions may be important in blocking initial HSV infection or in suppressing reactivation.

Vaccines against varicella-zoster virus (VZV) [27], the herpes virus that causes chickenpox, may be informative on approaches to develop vaccines against HSV. A licensed, live attenuated vaccine is given to children to prevent infection and disease. However, a subunit vaccine is more protective in older adults to prevent VSV reactivation (zoster) than the live attenuated vaccine [28, 29]. This suggests that different vaccine platforms (and potentially different forms of immune responses) may be required for prevention of herpes virus infections versus reactivation. One difficult aspect of HSV-1/2 studies is the lack of characterized protective responses in human infections. Patients have decreased clinically recognized recurrent episodes after the first year of HSV-2 infection, so more studies analyzing ADCC and CDC responses compared to neutralizing responses should be conducted in those individuals. Future proof-of-concept studies with protective monoclonal antibodies that are altered to lack Fc functions (using the LALA mutation) or afucosylated to increase ADCC activity should be tested for efficacy. These model systems could confirm the role of nonneutralizing antibody functions in control of HSV infection or suppression of reactivation. Furthermore, T-cell responses should be further studied as another potential correlate of immunity, especially given the cell-to-cell spread of herpes viruses that could shield them from neutralizing antibodies. T-cell responses in HSV infection are complex and future studies should include analyses of both circulating and tissue-resident memory cells [20]; indeed, T-cell studies regarding the live attenuated versus subunit VZV vaccines suggest that different types of T-cell responses may be required for control of infection versus suppression of reactivation [30]. Lastly, studies analyzing antibody responses as they pertain to control of asymptomatic virus shedding, the source of most transmission, should be conducted.

Notes

Financial support. No financial support was received for this work.

References

Author notes