IVIG and Infectious Disease - Update on May 25, 2012

The May 18, 2012 issue of Science magazine contains an article entitled "China Takes Aim at Rampant Antibiotic Resistance"(Science 336, 795, 2012) describing the emergence of antibiotic-resistant bacteria. While there is some renewed enthusiasm in the development of new antibiotics, the existing "pipeline" appears to be empty. I want to emphasize that the human immune system is constantly evolving to respond to new pathogens. Passive immunization is a useful therapeutic option.

The April 27, 2012 issue of Science magazine contains two news articles which should be of considerable interest to those responsible for the manufacture of intravenous immunoglobulin (IVIG) for therapeutic use in humans. The first entitled "Europe's Embarrassing Problem" (Science 336, 406-407, 2012) addresses the emergence of measles as a significant health problem in Europe. The primary of thrust is directed toward issues of vaccination and it would appear that developed countries have forgotten importance of vaccination in public health. I would like to note that one of the first clinical uses of immunoglobulin (gamma globulin) obtained from human plasma was for the prophylaxis and treatment of measles (1,2). While not a large literature, there are recent reports on the use of IVIG for measles (3-6). The reader is direct to the study by Audet and coworkers (4) which described the role of starting plasma (recovered versus source) and manufacturing procedure in determining anti-measles antibody titer. The message here is that current IVIG products have value in the prophylaxis and treatment of measles.

The second article "Monitoring EU emerging infectious disease risk due to climate change" (Science 236, 418-419, 2012) addresses emerging infectious diseases in Europe. The thrust of this article is directed to the role of climate change in emerging diseases previous seen in more tropical climates and the necessity for increased surveillance. While the use of IVIG in infectious disease is not a hot topical area, there is consistent recognition of value of this biopharmaceutical for a variety of bacterial and viral pathogens (7-9). It is important to understand that our individual immunoglobulin repertoire is constantly evolving to reflect challenges by new pathogens. Thus, the human in vitro manufacturing of anti-pathogens moves much faster to reflect current danger than any in vitro enterprise. I am aware of effect to develop recombinant polyclonal antibodies . I should emphasize the polyclonality is critical for IVIG effectiveness in action against pathogens as Fc function in mobilization of complement is necessary for effective therapy. I want to call your attention to the Strategic Plan for Regulatory Science and Research just released by the FDA Center for Biologics Evaluation and Research (http://www.fda.gov/downloads/BiologicsBloodVaccines/ScienceResearch/UCM303542.pdf?source=govdelivery) which places emphasis on emerging pathogens.

I just reviewed IVIG for a book (10) which should appear this fall. I found that the bulk of the use of this product is in areas outside of infectious disease; thus, the potential for use infectious disease is sometimes lost in the pursuit of more exciting (and perhaps more remunerative) pathologies. One of the recent email notices that I received from the FDA discussed the chronic shortage of IVIG products (See http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm ). So the challenge then is how to use a limited resource in a more effective manner. Another challenge is to retain all of the potential therapeutic immunoglobulin (4). Current Fraction II or Fraction II + III or Fraction I + II III could be subfractionated to separate the various active fractions. It is most unlikely that the entire immunoglobulin population is required for either a specific pathogen or immunomodulatory effect; a reasonable guess would be 1% or less. The other possiblity is to focus on hyperimmune products. It is suggested these are not unreasonable considerations which would provide both much need public health service as well as additional revenue for the fractionators.

 

Roger L. Lundblad, May, 2012, Chapel Hill, North Carolina

References

1. Ordman, C.W., Jennings, C.G., Jr., and Janeway, C.A., Chemical, clinical, and immunological studies on the products of human plasma fractionation. XII. The use of concentrated normal human serum gamma globulin (human immune serum globulin) in the prevention and attenuation of measles, J.Clin.Invest. 23, 541-544, 1944.

2. McDonald, J.C. and Cockburn, W.C., Report on the use of gamma globulin and adult serum for measles prophylaxis in England and Wales, 1949-1953, 1954.

3. Krause, I. Wu, R., Sherer, Y., et al., In vitro antiviral and antibacterial activity of commercial intravenouis immunoglobulin preparations - - a potential role for adjuvant intravenous immunoglobulin therapy in infectious diseases, Transfus.Med. 12, 133-139, 2002.

4. Audet, S., Virata-Theimer, M.L., Beeler, J.A., et al., Measles-virus-neutralizing antibodies in intravenous immunoglobulins, J.Infect.Dis.194, 781-789, 2006.

5. Nakajima, M., Sakuishi, K., Fukuda, S., et al., Recovery from adult measles encephalitis immediately after early immunomodulation, Clin.Infect.Dis. 47, 148-149, 2008.

6. Jorquera, J.L. and Flebogamma 5% DIF development: rationale for a new option in intravenous immunoglobulin therapy, Clin.Exp.Immunol. 157 (Suppl 1), 17-21, 2009.

7. Luke, T.C., Casadavall, A., Watowich, S.J., et al., Hark back: Passive immunotherapy for influenza and other serious infections, Crit.Care Med.38 (4 Suppl), e66-e73, 2010.

8. Stiehm, E.R., Orange, J.S., Ballow, M., and Lehman, H., Therapeutic use of immunoglobulins, Adv.Pediatr. 57, 185-218, 2010.

9. Raab, C.P., Passive immunization, Prim.Care 38, 681-691, 2011.

10. Lundblad, R.L., Biotechnology of the Plasma Proteins, CRC Press/Taylor & Francis, expected August 2012.