Vaccine manufacturing: challenges and solutions

Article metrics

Abstract

The recent influenza vaccine shortages have provided a timely reminder of the tenuous nature of the world's vaccine supply and the potential for manufacturing issues to severely disrupt vital access to important vaccines. The application of new technologies to the discovery, assessment, development and production of vaccines has the potential to prevent such occurrences and enable the introduction of new vaccines. Gene-based vaccines, virus-like particles, plant-derived vaccines and novel adjuvants and delivery systems represent promising approaches to creating safer, more potent vaccines. As a consequence, more people will have faster access to more effective vaccines against a broader spectrum of infectious diseases. However, the increased cost of producing new vaccines and regulatory uncertainty remain challenges for vaccine manufacturers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Key components of effective vaccines.
Figure 2: Reverse vaccinology for identification of novel vaccine antigens.

References

  1. 1

    Cooper, M.R., Stewart, D.C., Kahl, F.R., Brown, W.M. & Cordell, A.R. Medicine at the medical center then and now: one hundred years of progress. South. Med. J. 95, 1113–1121 (2002).

  2. 2

    Sheridan, C. The business of making vaccines. Nat. Biotechnol. 23, 1359–1366 (2005).

  3. 3

    Greco, M. Key drivers behind the development of global vaccine market. Vaccine 19, 1606–1610 (2001).

  4. 4

    Martineau, B. Stats. Sticking with growth. Vaccine market continues to rise. Mater. Manag. Health Care 13, 42 (2004).

  5. 5

    Rappuoli, R., Miller, H.I. & Falkow, S. Medicine. The intangible value of vaccination. Science 297, 937–939 (2002).

  6. 6

    Farchaus, J.W., Ribot, W.J., Jendrek, S. & Little, S.F. Fermentation, purification, and characterization of protective antigen from a recombinant, a virulent strain of Bacillus anthracis. Appl. Environ. Microbiol. 64, 982–991 (1998).

  7. 7

    Ribot, W.J. et al. Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits. Vaccine 24, 3469–3476 (2006).

  8. 8

    Holst, J. et al. Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease. Vaccine 21, 734–737 (2003).

  9. 9

    Tettelin, H. et al. Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287, 1809–1815 (2000).

  10. 10

    Pizza, M. et al. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287, 1816–1820 (2000).

  11. 11

    Langermans, J.A. et al. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT-6. Vaccine 23, 2740–2750 (2005).

  12. 12

    Belshe, R., Lee, M.S., Walker, R.E., Stoddard, J. & Mendelman, P.M. Safety, immunogenicity and efficacy of intranasal, live attenuated influenza vaccine. Expert Rev. Vaccines 3, 643–654 (2004).

  13. 13

    Buonagurio, D.A. et al. Genetic stability of live, cold-adapted influenza virus components of the FluMist/CAIV-T vaccine throughout the manufacturing process. Vaccine 24, 2151–2160 (2006).

  14. 14

    Hardy, C.T., Young, S.A., Webster, R.G., Naeve, C.W. & Owens, R.J. Egg fluids and cells of the chorioallantoic membrane of embryonated chicken eggs can select different variants of influenza A (H3N2) viruses. Virology 211, 302–306 (1995).

  15. 15

    Katz, J.M. & Webster, R.G. Amino acid sequence identity between the HA1 of influenza A (H3N2) viruses grown in mammalian and primary chick kidney cells. J. Gen. Virol. 73, 1159–1165 (1992).

  16. 16

    Halperin, S.A. et al. Safety and immunogenicity of a trivalent, inactivated, mammalian cell culture-derived influenza vaccine in healthy adults, seniors, and children. Vaccine 20, 1240–1247 (2002).

  17. 17

    Nicolson, C., Major, D., Wood, J.M. & Robertson, J.S. Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system. Vaccine 23, 2943–2952 (2005).

  18. 18

    Neumann, G., Fujii, K., Kino, Y. & Kawaoka, Y. An improved reverse genetics system for influenza A virus generation and its implications for vaccine production. Proc. Natl. Acad. Sci. USA 102, 16825–16829 (2005).

  19. 19

    Donnelly, J.J., Ulmer, J.B., Shiver, J.W. & Liu, M.A. DNA vaccines. Annu. Rev. Immunol. 15, 617–648 (1997).

  20. 20

    Wang, R. et al. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 282, 476–480 (1998).

  21. 21

    Rottinghaus, S.T., Poland, G.A., Jacobson, R.M., Barr, L.J. & Roy, M.J. Hepatitis B DNA vaccine induces protective antibody responses in human non-responders to conventional vaccination. Vaccine 21, 4604–4608 (2003).

  22. 22

    McShane, H. et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat. Med. 10, 1240–1244 (2004).

  23. 23

    Ulmer, J.B., Wahren, B. & Liu, M.A. Gene-based vaccines: recent technical and clinical advances. Trends Mol. Med. 12, 216–222 (2006).

  24. 24

    Hoare, M. et al. Bioprocess engineering issues that would be faced in producing a DNA vaccine at up to 100 m3 fermentation scale for an influenza pandemic. Biotechnol. Prog. 21, 1577–1592 (2005).

  25. 25

    McConkey, S.J. et al. Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat. Med. 9, 729–735 (2003).

  26. 26

    Harper, D.M. et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 367, 1247–1255 (2006).

  27. 27

    Alonso, P.L. et al. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366, 2012–2018 (2005).

  28. 28

    Tacket, C.O. Plant-derived vaccines against diarrheal diseases. Vaccine 23, 1866–1869 (2005).

  29. 29

    Thanavala, Y. et al. Immunogenicity in humans of an edible vaccine for hepatitis B. Proc. Natl. Acad. Sci. USA 102, 3378–3382 (2005).

  30. 30

    Pashine, A., Valiante, N.M. & Ulmer, J.B. Targeting the innate immune response with improved vaccine adjuvants. Nat. Med. 11, S63–S68 (2005).

  31. 31

    Cooper, C.L. et al. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J. Clin. Immunol. 24, 693–701 (2004).

  32. 32

    Vandepapeliere, P. et al. Potent enhancement of cellular and humoral immune responses against recombinant hepatitis B antigens using AS02A adjuvant in healthy adults. Vaccine 23, 2591–2601 (2005).

  33. 33

    Wille-Reece, U., Wu, C.Y., Flynn, B.J., Kedl, R.M. & Seder, R.A. Immunization with HIV-1 Gag protein conjugated to a TLR7/8 agonist results in the generation of HIV-1 Gag-specific Th1 and CD8+ T cell responses. J. Immunol. 174, 7676–7683 (2005).

  34. 34

    Kazzaz, J. et al. Encapsulation of the immune potentiators MPL and RC529 in PLG microparticles enhances their potency. J. Control. Release 110, 566–573 (2006).

  35. 35

    Vidal, D. Topical imiquimod: mechanism of action and clinical applications. Mini Rev. Med. Chem. 6, 499–503 (2006).

  36. 36

    Germann, T.C., Kadau, K., Longini, I.M., Jr & Macken, C.A. Mitigation strategies for pandemic influenza in the United States. Proc. Natl. Acad. Sci. USA 103, 5935–5940 (2006).

Download references

Author information

Correspondence to Jeffrey B Ulmer.

Ethics declarations

Competing interests

The authors are employees of Novartis Vaccines and Diagnostics.

Rights and permissions

Reprints and Permissions

About this article

Further reading