WO2012139099A2 - Vaccin contre le virus de l'herpès simplex - Google Patents

Vaccin contre le virus de l'herpès simplex Download PDF

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Publication number
WO2012139099A2
WO2012139099A2 PCT/US2012/032728 US2012032728W WO2012139099A2 WO 2012139099 A2 WO2012139099 A2 WO 2012139099A2 US 2012032728 W US2012032728 W US 2012032728W WO 2012139099 A2 WO2012139099 A2 WO 2012139099A2
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Prior art keywords
immunogen
sequence
hsv
gpl20
env
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PCT/US2012/032728
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WO2012139099A3 (fr
Inventor
Georgia D. Tomaras
Barton F. Haynes
Anthony M. Moody
Hua-Xin Liao
Jerome Kim
Nelson MICHAEL
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Walter Reed Army Institute of Research
Duke University
United States Department of the Army
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Walter Reed Army Institute of Research
Duke University
United States Department of the Army
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Publication of WO2012139099A3 publication Critical patent/WO2012139099A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/245—Herpetoviridae, e.g. herpes simplex virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55544—Bacterial toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6075—Viral proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates, in general, to herpes simplex virus (HSV) and, in particular, to a vaccine against HSV and to a method of inducing an immune response against HSV in a subject using same.
  • HSV herpes simplex virus
  • HSV types 1 and 2 are enveloped DNA viruses of the herpesvirus family that are common causes of human disease.
  • HSV-1 is frequently acquired early in life such that -50% of 5-year-old children in the US have evidence of infection. Acquisition continues throughout life and 70-90% of the elderly have evidence of prior infection.
  • HSV-2 acquisition is more sporadic with infection rates increasing throughout adolescence and data shows that -20% of US adults have evidence of infection, although, in certain populations, the rates can be substantially higher, in some cases up to 80%.
  • Herpesvirus infections are acquired through person-to-person contact and the site of entry is skin and/or mucous membranes.
  • the viruses bind to cellular receptors via proteins expressed on the surface of virions, including gD, and interaction of these virus receptors with host receptors triggers the events of virus fusion and host cell infection.
  • the virus can infect multiple cell types and can cause disease ranging from localized blistering (vesicles), such as is seen in a cold sore, local spread of vesicular rash, dissemination of the vesicular rash, invasion of the bloodstream, infection of internal organs (including the liver), and infection of the central nervous system (including the brain). More extensive disease is associated with increasing degrees of morbidity and mortality.
  • HSV-1 and HSV-2 infect nerve cells, typically peripheral ganglia, and can remain dormant for days to years. Reactivation occurs following signaling events that are poorly understood. Once reactivation occurs, the virus replicates and either asymptomatic shedding of the virus or shedding in the context of disease manifestations can occur. It is these periods of virus replication that are associated with the common manifestations of recurrent HSV disease, including cold sores around the mouth and outbreaks of genital herpes. During periods of such outbreaks, transmissible virus is shed and while symptomatic outbreaks are associated with higher levels of virus shedding, asymptomatic shedding is known to occur frequently. Studies of adult women infected with genital HSV-2 suggest that there is a 1 in 100 chance on any day of asymptomatic shedding of infectious virus.
  • populations at very high risk for disseminated or central nervous system disease include newborn infants, patients with inborn errors of the immune system, patients with acquired immune deficiencies (e.g., HIV infection), patients undergoing chemotherapy for malignancies, and the elderly.
  • Such patients are at risk of more severe primary disease, more severe recurrent disease, difficulty controlling infection once established, shorter periods of latency compared to healthy hosts, increased rates of asymptomatic shedding, and a higher likelihood of dissemination.
  • the immune response to HSV involves innate and adaptive immunity. As with all viral infections, both cell-mediated and humoral responses are critical. The critical importance of humoral immunity has been suggested by studies of HSV transmission around the time of birth (i.e., perinatal or congenital HSV) where infants bom to women experiencing primary HSV disease are more likely to acquire HSV than infants born to women with recurrent HSV. This is thought to be due to transplacental transfer to the infant of IgG antibodies produced by the mother that provide a degree of protection. For this reason, an effective vaccine that can induce such antibodies and/or human mAbs that can be passively administered could provide protection to infants against this disease.
  • the present invention provides a novel approach to inducing in a subject (e.g., a human) an effective immune response against HSV.
  • the invention relates to HSV. More specifically, the invention relates to a vaccine against HSV and to a method of inducing an immune response against HSV in a subject (e.g., a human) using same.
  • FIG. 1 Binding antibodies in RV144 were examined in 100 vaccine participants. The level of antibodies to the gD peptide were measured. 100% of the vaccinees had IgG antibodies to the gD peptide that were elicited by vaccination.
  • FIG. 1 IgA binding antibodies in RV144 were examined in 100 vaccine participants. The level of antibodies to the gD peptide were measured. About sixty three percent of the vaccinees had IgA antibodies to the gD peptide that were elicited by vaccination.
  • FIG. 3 The gD peptide contains important sequences for HSV entry.
  • Figure 4. Additional studies relating to gD reactive antibodies.
  • Figure 5. Comparison of the vaccine elicited IgG responses to the gD peptide in RV144 compared to another vaccine (Chiron) that used the whole gD protein
  • RV144 elicited significantly higher antibody responses to the gD peptide than another vaccine (CHIRON) and also compared to natural HSV infection, indicating that these are unique antibody responses to a functional component needed for HSV entry.
  • RV144 elicited significantly higher antibody responses to the gD peptide than natural HSV infection, indicating that these are unique antibody responses to a functional component needed for HSV entry.
  • FIGS 7A-7C gD mAb epitopes mapping from RV 144 subject.
  • FIG. 7A Monoclonal antibody Ab5157.
  • FIG. 7B Monoclonal antibody Ab5190.
  • FIG. 7C Monoclonal antibody Ab5188.
  • FIG. 1 Exemplary immunogens.
  • FIG. 9 Design of vaccine immunogens for induction of neutralizing antibodies against HSV in humans.
  • Constructs can be designed to express an HSV gD epitope N- terminal to, for example: 1) a strong or immunodomint antigen, such as tetanus toxin (TT) fragment C (Fairweather, et al., J. Bacteriol. 165:21-27,1986), 2) a weak antigen, such as Human T-cell lymphotropic virus type 1 (HTLV-1) envelope (Env) glycoprotein (Schulz et al, Virology, 184:483-491 , 1991), 3) a non-immunogenic protein, such as human serum albumin (HSA) (Carter, D.C. and He, X.M. Science 249:302-303,1990), or 4) fragments of these proteins.
  • a linker sequence such as LLE or other amino acids in any order and lengths can be present between HSV gD and these protein sequences.
  • HSV gD epitope included in the protein boost immunogen of RV144 resulted in enhanced exposure of multiple antibody binding sites that improved the quality of the protein for binding to known monoclonal antibodies (VRCOl , CHOI , A32 mAbs) in comparison with the envelope protein without the gD epitope.
  • this immunogen induced antibody responses (IgG, (IgG3), and IgA) in the vaccinees that were of higher magnitude to envelope proteins containing the gD epitope. It was found that these enhanced vaccine-elicited responses were the result of conformational changes to the gpl20 induced by the addition of the gD epitope.
  • Fig.2 About sixty three percent of the vaccinees had IgA antibodies to the gD peptide that were elicited by vaccination (Fig.2). As shown in Fig. 3, the gD peptide includes sequences important for HSV entry. (See also Figs. 5 and 6.)
  • a subject e.g., a human
  • the present invention relates to an immunogen, gpl20 or gpl40 with an N-terminal gpl20 gD (or portion thereof) tag, with or without a LE sequence and with or without the original 12 amino acids of the N-terminus of g l20 (see exemplary immunogens shown in Figure 8 and in Figure 2 of U.S. Prov. Application No. 61/407,299, filed October 27, 1010)
  • the leader sequence can be the HSV leader sequence, the HIV leader sequence or a transmitted founder virus leader sequence with a position 12 histidine.
  • the Env g l20 or g l40 for connecting to gD tag is a transmitted founder virus Env such as 1086.C, 089.C, 63521.
  • the gD HSV tag sequence, or portion thereof can be added N-terminal to consensus sequences such as the group M consensus CON-S gpl40 or gpl20 sequence (Liao et al, Virology 353(2):268 (2006), PCT/US04/30397, U.S. Application Nos.
  • the gD sequence can be added to a subunit of the gpl 20, gpl40 or gpl60 Env sequence.
  • constructs can also be designed to express an HSV gD epitope N-terminal to, for example: 1) a strong or immunodomint antigen, such as tetanus toxin (TT) fragment C (Fairweather, et al., J. Bacteriol. 165:21-27, 1986), 2) a weak antigen, such as Human T-cell lymphotropic virus type 1 (HTLV-1) envelope (Env) glycoprotein (Schulz et al, Virology, 184:483-491 , 1991), 3) a non-immunogenic protein, such as human serum albumin (HSA) (Carter, D.C. and He, X.M.
  • HSA human serum albumin
  • a linker sequence such as LLE or other amino acids in any order and lengths, can be present between the HSV gD epitope and such protein sequences. Examples of such constructs are shown in Fig. 9.
  • the gD tag (or epitope) can be 28 amino acids in length or a subunit thereof can be used, e.g., a subunit of at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28 amino acids in length.
  • the subunit can comprise, for example, LPVLDQ.
  • the gD+ and gpD+ gpl40 envelopes can be formulated as DNAs (Santra S. et al. Nature Med. 16: 324-8, 2010), for example, rAdenovirus vectored Envs (Barouch DH, et al. Nature Med. 16: 319-23, 2010), recombinant mycobacteria (ie BCG or M smegmatis) (Yu, JS et al. Clinical Vaccine Immunol. 14: 886-093, 2007; ibid 13: 1204-11 , 2006), recombinant vaccinia type of vectors (Santra S. Nature Med. 16: 324-8, 2010).
  • DNAs Santra S. et al. Nature Med. 16: 324-8, 2010
  • rAdenovirus vectored Envs Barouch DH, et al. Nature Med. 16: 319-23, 2010
  • recombinant mycobacteria ie
  • the gD+ envelopes can also be administered as a protein boost in combination with a variety of vectored Env primes (Barefoot B et al. Vaccine 26: 6108-18, 2008), or as protein alone (Liao HC et al Virology 353 : 268-82, 2006).
  • the protein can be administered advantageously with existing adjuvants such as MF59, AS01B or alum and administered either subcutaneously or intramuscularly.
  • the protein or vectored Env can be administered mucosally such as intranasal immunization or by other mucosal routes (Torrieri DL et al Mol. Ther. Oct. 19 2010, E put ahead of print).
  • Immunogens of the invention are suitable for use in generating an immune response in a patient (e.g., a human patient) to HSV.
  • the mode of administration can vary with the immunogen, the patient and the effect sought, similarly, the dose administered.
  • the administration route will be intramuscular, subcutaneous injection (intravenous and intraperitoneal can also be used).
  • the formulations can be administered via the intranasal route, or intrarectally or vaginally as a suppository-like vehicle. Optimum dosing regimens can be readily determined by one skilled in the art.
  • the immunogens are preferred for use prophylactically, however, their administration to infected individuals may reduce viral load.
  • the present invention relates to novel immunogens and compositions and to novel methods of inducing an immune response.
  • the invention includes the immunogens described above, with the proviso that immunogens previously described and/or utilized in connection with the Thai RV144 trial are not included.
  • a heterologous prime-boost strategy demonstrated positive results in an efficacy trial (RV144) (Rerks-Ngarm, S et al NEJM 361 : 2209-30 (2009)).
  • RV144 efficacy trial
  • the immune correlates of protection for the heterologous prime-boost RV144 efficacy trial are as yet undefined, the reduced rate of acquisition without a significant effect on initial viral loads or CD4 + T cell counts, have raised the hypothesis of an RV144 vaccine-elicited transient protective B cell response (Rerks- Ngarm, S et al NEJM 361 : 2209-30 (2009)).
  • the duration of protection was short, demonstrating the need for improvement in the level of protection.
  • HIV-1 gpl20 Env proteins in the B/E boosts had a herpes simplex virus (HSV) gD protein 28 aa epitope tag and an extra LE aa sequence just after the tag at the N-terminus of g l20.
  • HSV herpes simplex virus
  • This extra region put on the HIV Env as a tag for purification of the HIV-1 envelope protein contains the HSV gD binding sites for three host receptors for HSV (Connolly et al, J. Virol. 79: 1282 (2005), Yoon et al, J. Virol.
  • the reverted unmutated ancestor antibodies (RUAs) of the CHOI , CH02 and CH03 anti-gpl20 quarternary human mAbs also bound to gD+, A244 gpl 20 Env suggesting that the Thai trial immunogen could bind to the germline B cell receptors of na ' ive B cells.
  • gD tag is in the gpl40 unliganded trimer has been modeled.
  • a monoclonal antibody (Mab 13D7) that binds to the initial 14 N-terminal aa of gpl20 binds only to those gpl20 Env proteins that do not contain the gD epitope and it does not bind to either the A244 gD+ gpl20 produced in CHO cells and used in the Thai trial, nor to the A244 gD+ gpl20 produced in 293T cells.
  • the T8 mAb that binds to the CI region of gpl20 is in the gD+ versions of gpl20 and that mAb binding is enhanced to the gD+ gpl20 A244 Envs.
  • gpl20 binding to sCD4 was also markedly enhanced in gpl20s expressing the gD epitope.
  • the VRCOl mAb the most potent neutralizing antibody known for HIV- 1 , binds to the CD4 binding site region on the HIV-1 Env in a manner that is most similar to the CD4 molecule (Wu et al, Science 329:856 (2010), Zhou et al, Science 329:81 1 (2010)).
  • VRCOl mAb had increased binding to A244 gpl 20 Env that contained the gD epitope compared to the Env without the gD epitope.
  • the dissociation constant ( d) of binding of VRCOl mAb for the A244 gD+ gpl20 was 41 nM compared to a Kd of 164nM for the same envelope without the gD epitope.
  • Another potent epitope on gpl20 for broad neutralizing antibodies is the quaternary epitope involving the V2 and V3 regions of g l20 (Walker et al, Science 326:285 (2009)). Both the CHOI -05 (Bonsignori and Haynes, AIDS Research Human Retroviruses P04.52LB (2010)) and the PG9 and PG16 antibodies (Walker et al, Science 326:285 (2009)) bind to this epitope but likely in slightly different orientations. The question asked was whether the presence of the gD tag on A244 Env had any effect on the ability of either CHOI or PG9 to bind to A244 gpl20.
  • IgG3 antibodies had a pronounced difference in the concentration of antibodies circulating in the plasma of vaccinees that preferentially bound to gD+ gpl20 Envs.
  • IgA responses to the vaccine immunogens. Eighty-nine percent of vaccinees had IgA responses to the vaccine strain MN and twenty-three percent had IgA responses to a primary clade A gpl20 (OOMSA). Significantly higher IgA responses were detected against the MN g l20 containing the gD epitope compared to MN gpl20 without the gD epitope. Measurement was also made of IgA responses elicited directly to the gD epitope, and it was found that a significant proportion, sixty-three percent, of vaccinees had IgA responses to the HSV gD epitope (Fig 2).
  • the avidity of the purified plasma IgG to a series of envelopes was measured. It was found that several subjects demonstrated binding antibody breadth to a clade A isolate were also among those subjects that had the highest avidity for the vaccine strain immunogen and had the highest neutralizing antibody titers. A critical question to address was whether the enhanced binding of vaccinee serum to gD+ Env gpl20s was due solely to an additive effect of the presence of anti-gD antibodies. Alternatively, it was hypothesized that the gpl20 gD+ protein was in an optimal conformation to induce gpl 20 antibody
  • gD epitope tag induced epitopes in the gpl20Env are highly functional sites to which antibodies can bind and mediate ADCC (A32), and neutralization (CHOI , VRCOl). All documents and other information sources cited herein are hereby incorporated entirety by reference.
  • IFRPGGGD RDNWRSELYKYKWKIEPLGIAPTKAK.ERWQREKFAVGLGAVFIGFLGAAGSTMGAAS
  • HIV-1 gpl20-gp41 cleavage site was mutated from the residue Arg (R) to Glu (E) as shown in italics.
  • HSV leader sequence was underlined, HSV gD sequence is bolded and linker sequence between gD and HIV sequences is shown in italics .

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Abstract

La présente invention porte, en général, sur le virus de l'Herpès simplex (VHS) et, en particulier, sur des anticorps qui sont spécifiques à la glycoprotéine D (gD) du VHS. L'invention porte également sur des utilisations prophylactiques et thérapeutiques de tels anticorps.
PCT/US2012/032728 2011-04-08 2012-04-09 Vaccin contre le virus de l'herpès simplex Ceased WO2012139099A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028929A1 (fr) * 1993-06-07 1994-12-22 Genentech, Inc. Polypeptides d'enveloppe du vih
MXPA05013334A (es) * 2003-06-12 2006-05-19 Vexgen Inc Glucoproteinas de envoltura de vih-1 que tienen estructuras de disulfuro inusuales.
EP3756684A1 (fr) * 2009-05-22 2020-12-30 Genocea Biosciences, Inc. Vaccins contre le virus de l'herpès simplex de type 2 : compositions et procédés pour obtenir une réponse immunitaire

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