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US-12622960-B2 - Varicella zoster virus (VZV) vaccine

US12622960B2US 12622960 B2US12622960 B2US 12622960B2US-12622960-B2

Abstract

Aspects of the disclosure relate to nucleic acid vaccines. The vaccines include at least one RNA polynucleotides having a open reading frame encoding at least varicella zoster virus (VZV) antigen. Methods for preparing and using such vaccines are also described.

Inventors

  • Giuseppe Ciaramella

Assignees

  • MODERNATX, INC.

Dates

Publication Date
20260512
Application Date
20240118

Claims (15)

  1. 1 . A messenger ribonucleic acid (mRNA) vaccine comprising; (a) an mRNA polynucleotide comprising from 5′ to 3′ a 5′untranslated region UTR, an open reading frame (ORF) encoding a varicella zoster virus (VZV) glycoprotein E(gE) protein, the protein comprising an amino acid sequence of SEQ ID NO: 38, a protein comprising a Y569A or a Y582G mutation, relative to the amino acid sequence of SEQ ID NO: 10, a protein comprising a truncated polypeptide lacking the cytoplasmic tail domain shown in amino acids 574-623 of SEQ ID NO: 10, or a truncated polypeptide lacking the transmembrane anchor domain shown in amino acids 562-573 of SEQ ID NO: 10 and a 3′ UTR, wherein 100% of uracil nucleosides in the ORF of the mRNA polynucleotide are N1-methylpseudouridine; and (b) a lipid nanoparticle comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), PEG-distearoyl glycerol (PEG DMG) and a compound of Formula (I): or a salt thereof, wherein: R 1 is selected from the group consisting of C 5-30 alkyl, C 5-20 alkenyl, and —R″M′R′; R 2 and R 3 are independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl; R 4 is —(CH 2 ) n Q, wherein Q is-OR, and n is selected from 1, 2, 3, 4, and 5; each R 5 is H; each R 6 is H; M and M′ are independently selected from —C(O)O— and —OC(O)—; R 7 is H; R is H; R′ is selected from the group consisting of C 1-18 alkyl and C 2-18 alkenyl; R″ is selected from the group consisting of C 3-14 alkyl and C 3-14 alkenyl; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.
  2. 2 . The mRNA vaccine of claim 1 , wherein the VZV gE protein comprises the amino acid sequence of SEQ ID NO: 38.
  3. 3 . The mRNA vaccine of claim 1 , wherein the ORF comprises a nucleotide sequence comprising at least 90% sequence identity to the mRNA sequence corresponding to SEQ ID NO: 62.
  4. 4 . The mRNA vaccine of claim 1 , wherein the ORF comprises the nucleotide sequence of SEQ ID NO: 62.
  5. 5 . The mRNA vaccine of claim 2 , wherein the ORF comprises a nucleotide sequence comprising at least 90% sequence identity to a mRNA sequence corresponding to SEQ ID NO: 62.
  6. 6 . The mRNA vaccine of claim 1 , wherein the ORF comprises a nucleotide sequence comprising at least 90% sequence identity to nucleotides 49-1767 of SEQ ID NO: 101.
  7. 7 . The mRNA vaccine of claim 1 , wherein the ORF comprises a nucleotide sequence comprising nucleotides 49-1767 of SEQ ID NO: 101.
  8. 8 . The mRNA vaccine of claim 2 , wherein the ORF comprises a nucleotide sequence comprising at least 90% sequence identity to nucleotides 49-1767 of SEQ ID NO: 101.
  9. 9 . The mRNA vaccine of claim 1 , wherein the VZV gE protein comprises a Y569A mutation, relative to the amino acid sequence of SEQ ID NO: 10.
  10. 10 . The mRNA vaccine of claim 1 , wherein the VZV gE protein comprises a Y582G mutation, relative to the amino acid sequence of SEQ ID NO: 10.
  11. 11 . The mRNA vaccine of claim 1 , wherein the VZV gE protein is a truncated polypeptide lacking the cytoplasmic tail domain shown in amino acids 574-623 of SEQ ID NO: 10.
  12. 12 . The mRNA vaccine of claim 1 , wherein the VZV gE protein is a truncated polypeptide lacking the transmembrane anchor domain shown in amino acids 562-573 of SEQ ID NO: 10.
  13. 13 . The mRNA vaccine of claim 1 , wherein the mRNA vaccine comprises a second mRNA polynucleotide comprising a second ORF encoding a VZV antigen selected from the group consisting of gB, gI, gM, and gH.
  14. 14 . A method of inducing an antigen specific immune response in a subject, comprising: administering to the subject the mRNA vaccine of claim 1 .
  15. 15 . The method of claim 14 , wherein the mRNA vaccine is administered in a total dose of 25 μg-100 μg of the mRNA polynucleotide.

Description

RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/245,973, filed Apr. 30, 2021, which is a continuation of U.S. application Ser. No. 16/494,162, filed Sep. 13, 2019, which is a national stage filing under 35 U.S.C. § 371 of international application number PCT/US2018/022643, filed Mar. 15, 2018, which was published under PCT Article 21(2) in English and claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application No. 62/471,809, filed Mar. 15, 2017, and U.S. provisional application No. 62/490,112, filed Apr. 26, 2017, each of which is incorporated by reference herein in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (M137870077US04-SUBSEQ-VLJ.xml; Size: 394,171 bytes; and Date of Creation: Sep. 16, 2024) is herein incorporated by reference in its entirety. BACKGROUND Varicella is an acute infectious disease caused by varicella zoster virus (VZV). Varicella zoster virus is one of eight herpesviruses known to infect humans and vertebrates. VZV is also known as chickenpox virus, varicella virus, zoster virus, and human herpesvirus type 3 (HHV-3). VZV only affects humans, and commonly causes chickenpox in children, teens and young adults and herpes zoster (shingles) in adults (rarely in children). The primary VZV infection, which results in chickenpox (varicella), may result in complications, including viral or secondary bacterial pneumonia. Even when the clinical symptoms of chickenpox have resolved, VZV remains dormant in the nervous system of the infected person (virus latency) in the trigeminal and dorsal root ganglia. In about 10-20% of cases, VZV reactivates later in life, travelling from the sensory ganglia back to the skin where it produces a disease (rash) known as shingles or herpes zoster. VZV can also cause a number of neurologic conditions ranging from aseptic meningitis to encephalitis. Other serious complications of VZV infection include postherpetic neuralgia, Mollaret's meningitis, zoster multiplex, thrombocytopenia, myocarditis, arthritis, and inflammation of arteries in the brain leading to stroke, myelitis, herpes ophthalmicus, or zoster sine herpete. In rare instances, VZV affects the geniculate ganglion, giving lesions that follow specific branches of the facial nerve. Symptoms may include painful blisters on the tongue and ear along with one sided facial weakness and hearing loss. Varicella cases have declined 97% since 1995, mostly due to vaccination. However, an estimated 500,000 to 1 million episodes of herpes zoster (shingles) occur annually in just the United States. The lifetime risk of herpes zoster is estimated to be at least 32%, with increasing age and cellular immunosuppression being the most important risk factors. In fact, it is estimated that 50% of persons living until the age of 85 will develop herpes zoster. A live attenuated VZV Oka strain vaccine is available and is marketed in the United States under the trade name VARIVAX® (Merck). A similar, but not identical, VZV vaccine is marketed globally as VARILRIX® (GlaxoSmithKline). Since its approval in 1995, it has been added to the recommended vaccination schedules for children in Australia, the United States, and several other countries. In 2007, the Advisory Committee on Immunization Practices (ACIP) recommended a second dose of vaccine before school entry to ensure the maintenance of high levels of varicella immunity. In 2001-2005, outbreaks were reported in schools with high varicella vaccination coverage, indicating that even in settings where most children were vaccinated and the vaccine performed as expected, varicella outbreaks could not be prevented with the one-dose vaccination policy. As a result, two-dose vaccination is the adopted protocol; however, even with two doses of vaccine, there are reported incidences of breakthrough varicella. Furthermore, varicella vaccination has raised concerns that the immunity induced by the vaccine may not be lifelong, possibly leaving adults vulnerable to more severe disease as the immunity from their childhood immunization wanes. In 2005, the FDA approved the combined live attenuated combination measles-mumps-rubella-varicella (MMRV) vaccine PROQUAD™ (Merck) for use in persons 12 months to 12 years in age. While the attenuated measles, mumps, and rubella vaccine viruses in MMRV are identical and of equal titer to those in the MMR vaccine, the titer of Oka/Merck VZV is higher in MMRV vaccine than in single-antigen varicella vaccine. In 2006, the United States Food and Drug Administration approved ZOSTAVAX® (Merck) for the prevention of shingles (herpes zoster) in persons 60 years or older (currently 50-59 years of age is approved). ZOSTAVAX® contains the same Oka/Merck varicella zoster virus used in the varicella and MMRV vaccines, but at a much higher titer (>10-fold higher viral dose) than that present in both of these vaccines, as the concentrated formulation is