Table 1.
| Adjuvant/formulations | Pathogen (antigen) | Trial results |
|---|---|---|
| MINERAL SALTS | ||
| Aluminium salts (hydroxide, phosphate, alum) | Numerous antigens | Licensed for human use. Induction of strong antibody responses4 |
| Calcium phosphate | DT | Was found to be better than Al(OH)3 in a booster trial |
| SBAS-4/ASO4 (alum + MPL) | HBV (HBs antigen), HSV (gD) | Increased antibody titres and lymphoproliferative responses when compared with alum, increased seroconversion rate after 2 immunizations5 |
| EMULSIONS | ||
| MF59 (stabilized squalene/sater) | Flu (split trivalent) | Component of a licensed influenza vaccine. Increase vaccine immunogenicity in young adults and in elderly (HAI titre). Safe (only mild local reactions), even after repeated injections in elderly |
| HBV(rPreS2-S) | More immunogenic than alum-adsorbed licensed hepatitis B vaccine | |
| HSV-2 (rgB + rgD) | Prophylactic vaccination: humoral and cellular immunity after 3 injections is superior to natural immunity after HSV-2 infection. A therapeutic vaccination trial in patients with recurrent genital herpes showed no improvement in rate of recurrence but both severity and duration of 1st outbreak were reduced | |
| HIV1 (gp120), CMV (rgB) | Improved immunogenicity over alum | |
| MF59 + MTP-PE | Flu (trivalent split), HIV1 (env) | MTP-PE increases reactogenicity, with no overall improvement in terms of immunogenicity (equivalent to MF59) |
| QS21 (purified saponin from Quillaja saponaria) | Malaria (SPf), HIV (gp120), melanoma, pneumo conj | Some local reactions. Enhanced antibody responses. Limited cellular responses in humans, despite good results obtained in animal models. QS21 enhances by 2-fold the booster effect (antibody response) of second dose of conjugate polysaccharide vaccine against Neisseria pneumoniae4,5 |
| SBAS-2/ASO2 (squalene/water + MPL + QS21) | Malaria (RTS,S) | High anti-CSP titres (better than with squalene/water or with MPL + alum) after 3 immunizations. Short-lived protection (less than 6 months) of 7 out of 8 naive individuals against challenge (infected mosquito bites). RTS,S-specific lymphoproliferative and antibody responses but no induction of CD8+ CTLs7 |
| HIV-1 (rgp120) | Increased seroconversion rate in seronegative subjects after single immunization (superior to MPL + QS21 or alum). Strong cell-mediated immunity (T-cell proliferation; superior to MPL + QS21), but no CD8+ CTLs. No detectable neutralizing antibodies against primary isolates | |
| Incomplete Freund adjuvant (IFA, stabilized water/Drakeol) | gp120-depleted inactivated HIV-1 | REMUNE vaccine. Increased anti-p24 titres and DTH responses. In seropositive subjects: increased lymphoproliferation and β-chemokine (Rantes, MIP-1α, MIP-1β) production following p24 stimulation |
| Melanoma (gp100) | Induction of T-cell responses (evaluated by ELISPOT/IFN-* production) against gp100 HLA A2 restricted epitopes | |
| Montanide ISA51 (stabilized water/Drakeol) | HIV-1 (Tat toxoid) | Well tolerated. Increased anti-Tat antibody titres in 100% of the subjects. DTH response and lymphoproliferation to Tat in 50% of the subjects |
| Montanide ISA720 (stabilized water/squalene) | Malaria (MSP1, MSP2, Resa AMA1) | Well tolerated (minor local effects – tenderness, swelling and discomfort of use). Low antibody responses (equivalent to alum, despite superior antibody responses observed in animals). Strong lymphoproliferation8 |
| NATURAL/SYNTHETIC BACTERIAL PRODUCTS | ||
| Monophosphoryl lipid A (MPL) | Various antigens | Well tolerated in humans when administered in association with bacterial antigens or TAAs. Limited increase of cellular responses5 |
| Detox (stabilized squalene/water + MPL + CWS) | Malaria (R32NS18) | Some side-effects in malaria naive individuals (tenderness, induration, oedema + malaise and fever). Induction of anti-CSP antibodies after 3 immunizations (better than alum). Protection of 2/11 naive individuals against challenge with infected mosquitoes9 |
| Melanoma cell lysates | Induction of cellular and humoral responses against melanoma associated antigens. Increase in survival in patients with metastatic melanoma. Vaccine (Melacine) has been registered for this indication in Canada | |
| RC-529 (synthetic MPL-like acylated monosaccharide) | HBV (HBs) | Th1 and mucosal adjuvant in mice. Found to enhance, in association with alum, antibody responses against HBs antigen in humans (faster and stronger seroconversion)5 |
| OM-174 (lipid A derivative, E. coli), OM triacyl | Malaria (CSP), cancer | OM-174 was found to be safe in a phase I study in cancer patients (i.m. route). OM triacyl adjuvants are synthetic analogues based on a common triacyl motif, which induce maturation of human dendritic cells in vitro5 |
| Holotoxins (CT, PT, LT) | Various antigens | Utilization of detoxified bacterial toxins (mutated toxins or B subunits) devoided of ADP-ribosyltransferase activity. Enhancement of serous and mucosal IgA production. On-going evaluation of CT and LT as adjuvants in patch-based transcutaneous immunization. A flu vaccine with LT mutants is about to be tested intranasally in humans3,5 |
| CpG oligonucleotides | Hepatitis B (HBs) | Act as potent Th1 adjuvants in mice, chimpanzees and orang utangs. Two phase I trials conducted in humans (in association with alum) have shown enhanced antibody responses against the HBs antigen. CTL responses not documented. Based on the motif and chemical backbone, three classes of oligonucleotides are now defined with respect to their distinct capacity to activate either human B-, NK- or dendritic cells in vitro |
| IMMUNOADJUVANTS | ||
| Cytokines (IL-2, IL-12, GM-CSF) | TAAs, malaria (CSP, MSP1), hepatitis A and B | Utilization of cytokines as recombinant proteins, with limitations including short biological half-life and some severe toxicity (vascular leak syndrome, hepatotoxicity for IL-2 and IL-12, respectively). Enhancement of antibody responses with GM-CSF. More recently, utilization of recombinant vectors expressing locally (intratumourally) immunostimulatory cytokines (e.g. poxviruses)1 |
| Accessory molecules (B7.1) | Colorectal cancer (CEA) | The accessory molecule (B7.1), which provides co-stimulatory signals to T lymphocytes, has been included in association with the CEA antigen within the canarypox vector ALVAC, thereby enhancing cellular responses1 |
| PARTICULATE FORMULATIONS | ||
| Liposomes (DMPC/Chol) | Flu (monovalent split) | Well tolerated. No increase in antibody titres (equivalent to vaccine alone). Slight increase in CD8+ CTL response |
| DC Chol | H. pylori (urease) | Despite enhanced antibody and Th2/Th1 responses in animal models, no significant enhancement of cellular immune responses in humans5 |
| Virosomes | Hepatitis A, flu | Well tolerated. Rapid seroconversion leading to protective anti-hepatitis A or anti-influenza virus antibodies10 |
| ISCOMS (structured complex of saponins and lipids) | Flu (trivalent split), HPV16 (E6/E7) | Increase of influenza-specific CD8+ CTL response (when compared with flu vaccine alone)11 |
| PLGA | TT | PLGA particles were shown to elicit Th1 (presentation of CTL epitopes) and Th2 responses in mice. On-going trial with the tetanus toxoid: a difficulty is to prepare GMP-grade PLGA particles under aseptic conditions |
CSP, P. falciparum circumsporozoite; CWS, cell wall skeleton from Mycobacterium phlei; DT, diphtheria toxoid; MTP-PE, muramyl tripeptide dipalmitoyl phosphatidyl ethanolamine; PLGA, poly-(D,L)-lactide-co-glycolic acid; TAAs, tumour associated antigens; TT, tetanus toxoid.