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Immune Response to a Hepatitis B DNA Vaccine in Aotus Monkeys: A Comparison of Vaccine Formulation, Route, and Method of Administration

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Molecular Medicine Aims and scope

Abstract

Background

Attempts to optimize DNA vaccines in mice include using different routes of administration and different formulations. It may be more relevant to human use to carry such studies out in nonhuman primates. Here we compare different approaches to delivery of a DNA vaccine against the hepatitis B virus (HBV) in Aotus monkeys.

Materials and Methods

Thirty-two adult Aotus l. lemurinus monkeys divided into 8 groups of four were immunized with 400 µg of a DNA vaccine which encoded hepatitis B surface antigen (HBsAg). DNA in saline was administered by intradermal (ID) or intramuscular (IM) injection with needle and syringe, IM injection with the Biojector® needleless injection system or combined ID (needle) and IM (Biojector). DNA formulated with cationic liposomes (CellFECTIN)® was injected IM with needle or Biojector. DNA with added E. coli DNA (100 µg) was injected IM with the Biojector or ID. A ninth group of 4 monkeys was injected IM (needle) with Engerix-B, a commercial vaccine containing recombinant HBsAg (10 µg) adsorbed onto alum. Monkeys were boosted in an identical fashion to their prime at 8 weeks, but all received the protein vaccine (Engerix-B) at 16 weeks. Sera was assessed for antibodies against HBsAg (anti-HBs) by enzyme-linked imunosorbent assay (ELISA).

Results

The primary humoral response induced by IM delivery of the DNA vaccine was very poor. In most cases there was no detectable anti-HBs even after 2 DNA doses but the kinetics of the response to subsequent protein indicated that a memory B cell response had been induced. In contrast, following IM-adrninistration of DNA using the Biojector, detectable anti-HBs were observed in 3 of 8 animals and evidence for immunological priming was apparent in an additional 4 of the 8 monkeys. ID injection of DNA vaccine in saline induced a potent antibody response which was augmented 6-fold by the addition of E. coli DNA. Combining ID and IM administration did not improve humoral immunity over ID injection alone.

Conclusions

For immunization of primates with DNA vaccines, ID may be a preferable route to IM, although it is not clear whether the Aotus monkey is a relevant model for humans in this respect. Nevertheless, the use of the Biojector needleless injection system may improve responses with IM delivery of DNA vaccines. As well, the immunostimulatory action of E. coli DNA may be used to augment the humoral response induced by a DNA vaccine.

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Acknowledgments

The authors thank Dr. Georg Widera (PowderJect Inc.) for providing the pCMVA-S plasmid. Dr. Arthur Krieg (University of Iowa) for the E. coli DNA, Dr. Richard Stout (Bioject Inc.) for the Biojector needleless jet injection system, and Dr. Robert H. Purcell (NIAID, NIH) for the anti-New World monkey antibody. The Gorgas Memorial Laboratory authors in Panama thank Ms. G. Cisneros for laboratory technical assistance, Mr. C. Marin, Mr. R. Rojas, and Mr. T. Gonzales for their assistance in animal handling and care, and Ms. M. Brewer for her secretarial assistance. Technical assistance was also provided in Canada by Lacrimioara Comanita and Amanda Boyd.

This work was supported by the Naval Medical Research Institute and Development Command, work units 611102A.S13.00101-BFX. 1431 and 612787A.870.00101.EFX.1432, Army Contract DAMD17-91-C-1072. Support to H. L. D. was also provided through operating grants from MRC (Canada), a travel grant from Bioject Inc., and an Ontario Ministry of Health Career Scientist Award. The experiments reported here were conducted according to the principles set forth in the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council (U.S. Department of Health and Human Services, Publ. National Institutes of Health 86–23, 1985). The opinions and assertions herein are of the authors and are not to be construed as official or as reflecting the views of the U.S. Navy or the Department of Defense.

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Authors and Affiliations

  1. Malaria Program, Naval Medical Research Institute, Rockville, Maryland, USA

    Robert A. Gramzinski & Stephen L. Hoffman

  2. Gorgas Memorial Laboratory, Panama City, Panama

    Robert A. Gramzinski & Nicanor Obaldia

  3. Ottawa Civic Hospital, Loeb Research Institute, 725 Parkdale Ave., Ottawa, Ontario, Canada, K1Y 4E9

    Cynthia L. Brazolot Millan &  Heather L. Davis

  4. ProMed Trading Inc., Panama City, Panama

    Nicanor Obaldia

  5. Faculties of Health Sciences and Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Heather L. Davis

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  1. Robert A. Gramzinski
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  2. Cynthia L. Brazolot Millan
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  3. Nicanor Obaldia
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  4. Stephen L. Hoffman
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  5. Heather L. Davis
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Correspondence to Heather L. Davis.

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Gramzinski, R.A., Brazolot Millan, C.L., Obaldia, N. et al. Immune Response to a Hepatitis B DNA Vaccine in Aotus Monkeys: A Comparison of Vaccine Formulation, Route, and Method of Administration. Mol Med 4, 109–118 (1998). https://doi.org/10.1007/BF03401734

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