QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immmunization in humans☆
Introduction
An effective vaccine regimen to prevent HIV-1 infection may need to include a diverse and multifaceted immunologic response to be effective. One method for either diversifying or augmenting the immune repertoire after immunization is to employ novel adjuvants. Newer adjuvants may function by a variety of methods, such as, regulating costimulatory molecules, modifying pathways of antigen presentation, improving the deposition of antigen in the skin, or modulating local cytokine responses [1], [2], [3], [4], [5]. One of the more promising adjuvants studied extensively in the animal model is QS-21, an amphipathic molecule derived from the soapbark tree Quillaja saponaria [6], [7], [8], [9].
QS-21 has demonstrated many adjuvant properties when tested in animal models that may be potentially useful in HIV-1 vaccine formulations. It has induced CTL responses when combined with soluble protein, promoted a mixed TH1/TH2-like cytokine response pattern, and increased the rapidity and magnitude of the antibody response [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. The improved antibody response may allow for a dose-reduction in the antigen in vaccine formulations that may be needed in preparing multivalent antigen preparations. Such multivalent immunogens may be useful against a variety of pathogens known to exhibit antigenic variation, including pneumococcus, papillomavirus, as well as HIV-1.
The breadth of neutralizing antibody (NA) induced after immunization in human and non-human primate models remains restricted to date. When recombinant envelope strains are used as subunits, the antibodies neutralize the homologous virus strain used to derive the vaccine, and some closely related strains, but fail to neutralize diverse HIV-1 strains [20], [21], [22]. However, the goal of neutralization may be achievable, as sera from long-term non-progressors are capable of neutralizing many, but not all, strains of primary isolates [23], [24], [25]. One strategy to increase the breadth of responses would be to use a wide variety of HIV-1 primary isolate envelopes in a multivalent vaccine [26]. Whether increasing the number of subunits can improve the breadth of NA beyond that induced by each subunit given alone is under investigation. However, in order to make such a preparation, which can be applied after any number of different vector-based vaccines, the total amount of subunit formulated into each vaccine will be limited. Thus, the constraining factor for the number of subunits included in an immunogen may be the total protein content.
With these concepts in mind, a candidate HIV-1 subunit vaccine combined with QS-21 was evaluated in three phase I clinical trials in HIV-1 seronegative volunteers. The studies were designed to evaluate the safety of these formulations, to assess the kinetics of immune responses, to measure CD8+CTL, and to evaluate the immunogenic dose of a CHO cell-derived gp120 antigen when combined with QS-21.
Section snippets
Subjects
Study subjects were healthy adult volunteers between the age of 18–55. These volunteers had no evidence of serious medical illness as evaluated by history, physical examination, or screening laboratory studies [27], [28]. The subjects were all seronegative for HIV-1 and were at low or intermediate risk of HIV infection as judged by the earlier described AIDS Vaccine Evaluation Group (AVEG) criteria. Women of childbearing age had negative pregnancy tests before each immunization and agreed to
Enrollment and follow-up
Since the investigation was the first to examine the adjuvant effect of QS-21 with rsgp120, there was no information concerning the optimal dose of the adjuvant with the antigen. Moreover, the benefit of using alum with the QS-21 was unclear. Thus, to address these issues, we initiated study A, which examined four doses of the HIV-1MN rsgp120 vaccine (0, 100, 300, and 600 μg) three doses of QS-21 (0, 50, and 100 μg), given with or without alum. (Table 1A) In the second study (B), the doses of
Discussion
In these phase I studies of QS-21 combined with a CHO-cell derived gp120 envelope vaccine, significant toxicity was observed. Specifically, the use of QS-21 was associated with pain and tenderness at the injection site that was frequently characterized as moderate or severe. The pain was severe enough to warrant discontinuation of vaccination in some individuals, and was not infrequently associated with vasovagal episodes. This severe injection pain has been observed in three other studies [8].
Acknowledgements
The study protocol was approved, by the Institutional Review Board at each clinical site, and informed consent was obtained following the guidelines of the US Department of Health and Human Services and those of each clinical site. Financial Support: N01 AI-45208, N01 AI-45209, N01 AI-45210, N01 AI-45211, N01 AI-45212, N01 AI-65305, N01 AI-82500. We would like to acknowledge Fred Vogel of NIAID, and Amy Lim and Jeffrey Cleland of Genentech, for contributing to these studies. In addition, we
References (48)
- et al.
Adjuvants for human vaccines–current status, problems and future prospects
Vaccine
(1995) - et al.
Structure of the saponin adjuvant QS-21 and its base-catalyzed isomerization product by 1H and natural abundance 13C NMR spectroscopy
Carbohydr. Res.
(1996) - et al.
Induction of cross-reactive cytotoxic T-lymphocyte responses specific for HIV-1 gp120 using saponin adjuvant (QS-21) supplemented subunit vaccine formulations
Vaccine
(1997) - et al.
Iscoms containing purified Quillaja saponins upregulate both Th1-like and Th2-like immune responses
Cell Immunol.
(1997) - et al.
Impact of the saponin adjuvant QS-21 and aluminium hydroxide on the immunogenicity of recombinant OspA and OspB of Borrelia burgdorferi
Vaccine
(1994) - et al.
Formulation of the purified fusion protein of respiratory syncytial virus with the saponin QS-21 induces protective immune responses in Balb/c mice that are similar to those generated by experimental infection
Vaccine
(1995) - et al.
The adjuvant combination monophosphoryl lipid A and QS21 switches T cell responses induced with a soluble recombinant HIV protein from Th2 to Th1
Vaccine
(1999) - et al.
Vaccination with immunodominant peptides encapsulated in Quil A- containing liposomes induces peptide-specific primary CD8+ cytotoxic T cells
Vaccine
(1994) - et al.
Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside- keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma
Vaccine
(1994) - et al.
Accessory cell requirements for saponin adjuvant-induced class I MHC antigen-restricted cytotoxic T-lymphocytes
Cell. Immunol.
(1994)
Adjuvants and immune enhancement
Int. J. Technol. Assess. Health Care
Paracrine cytokine adjuvants in cancer immunotherapy
Annu. Rev. Immunol.
Role of adjuvants in HIV vaccine design
Antibiot. Chemother.
Present status of the use of cytokines as adjuvants with vaccines to protect against infectious diseases
Clin. Infect. Dis.
Saponins as vaccine adjuvants
Crit. Rev. Ther. Drug Carrier Syst.
Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex
J. Immunol.
QS-21: a water soluble triterpene glycoside adjuvant
Exp. Opin. Investig. Drugs
Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T lymphocyte responses
J. Immunol.
Immunogenicity and toxicity testing of an experimental HIV-1 vaccine in nonhuman primates
AIDS Res. Hum. Retroviruses
Effect of adjuvants on immunogenicity of MN recombinant glycoprotein 120 in guinea pigs
AIDS Res. Hum. Retroviruses
Induction of antigen-specific killer T lymphocyte responses using subunit SIVmac251 gag and env vaccines containing QS-21 saponin adjuvant
AIDS Res. Hum. Retroviruses
Saponin adjuvant enhancement of antigen-specific immune responses to an experimental HIV-1 vaccine
J. Immunol.
Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1, the National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group
J. Infect. Dis.
Cited by (121)
Research progress on emulsion vaccine adjuvants
2024, HeliyonAdjuvants, immunomodulators, and adaptogens
2022, Vaccinology and Methods in Vaccine ResearchA phase 1 antigen dose escalation trial to evaluate safety, tolerability and immunogenicity of the leprosy vaccine candidate LepVax (LEP-F1 + GLA–SE) in healthy adults
2020, VaccineCitation Excerpt :These data suggest that the lower antigen dose might be suitable for subsequent efficacy studies of the vaccine candidate, and use of the lower dose would be preferable for future implementation as more doses would be available. Several trials have observed peaked dose–response curves for vaccines where antigen-specific T cell responses induced by the highest provided dose are not superior, and sometimes lower, than those induced by lower vaccine doses [42–45]. It is suggested that high doses can push T cells to an exhausted state with reduced functional avidity and increased differentiation into a terminal state [46,47].
Controlling timing and location in vaccines
2020, Advanced Drug Delivery Reviews
- ☆
These data were presented in part at the 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1998, and at the Infectious Diseases Society of America 35th Annual Meeting, San Francisco, CA, 1997.
- 1
Present address: Aviron Mountain View, CA, USA.