Antibody responses elicited through homologous or heterologous prime-boost DNA and protein vaccinations differ in functional activity and avidity
Introduction
Despite the obvious need for a better understanding of how to raise functional antibodies through immunization, we still only have limited knowledge regarding to the relationship between the type of immunizations administered and the resulting antibody responses. Given safety concerns associated with live attenuated vaccines and the overall poor immunogenicity of inactivated vaccines, subunit vaccines, using only selected antigens from a complex pathogen, have been considered a more ideal choice. However, after more than 30 years of vaccine development, there are only a few subunit vaccines licensed for wide clinical use, including the surface protein-based hepatitis B virus vaccine and the L1 protein-based human papillomavirus (HPV) vaccine [1], [2]. Two conditions have been identified as critical for a successful recombinant protein-based subunit vaccine. First, an adjuvant is absolutely necessary as part of a recombinant protein-based vaccine formulation to achieve sufficient immunogenicity in humans [3], [4], [5], [6], [7]. Second, the conformation of a protein-based vaccine plays a key role in determining the functionality of antibody responses elicited by protein-based subunit vaccines. It was demonstrated in early HPV vaccine studies in animals that intact papilloma virions provided protection against subsequent challenge [8], but vaccination with disrupted or denatured papilloma virion particles failed to provide protection [9], [10], [11]. Such dependency on adjuvant and natural antigen conformation may have contributed to the slow development of more recombinant protein-based subunit vaccines.
At the same time, novel vaccine modalities, such as DNA vaccines and viral vector-based vaccines, have become attractive alternative approaches to deliver subunit antigens [12], [13]. More interestingly, heterologous prime-boost (i.e., the sequential use of two types of vaccines to deliver the same subunit antigen), can be more immunogenic than repeated administrations of either type of vaccine alone (homologous prime-boost) [14]. Studies previously conducted in our laboratory have demonstrated that the DNA prime-protein boost approach is more effective than using DNA or protein alone in eliciting higher antibody responses in both HIV-1 and influenza vaccine studies [15], [16], [17], [18]. While these studies began to identify differences in antibody responses resulting from different vaccination approaches, they lacked a rigorous comparison of the effects of number of immunizations as well as a detailed analysis on the quality of antibody responses. In the current study, we attempt to elucidate how the immunization regimen influences the quality of antibody response. By using HIV-1 gp120 envelope protein as a model antigen, differences in the resulting antibody responses elicited by either homologous or heterologous prime-boost immunizations are analyzed including the ability of the sera to neutralize a diverse panel of sensitive and primary HIV isolates, the specificity of antibodies being generated in a polyclonal sera, as well as the resulting avidity of gp120-specific antibodies.
Section snippets
HIV-1 gp120 DNA vaccine
A codon optimized JR-FL gp120 construct in the pJW4303 vector was used for all DNA-based immunizations, as previously reported [16]. DNA was produced in HB101 bacterial cells then isolated and purified using the Qiagen Plasmid Mega Kit (Cat #12183).
HIV-1 gp120 protein vaccines
Recombinant HIV-1 gp120 proteins were produced from Chinese Hamster Ovary (CHO) cells. The JR-FL gp120 protein produced by Progenics was provided by Dr. John Warren at Division of AIDS, NIAID, NIH. Other gp120 envelope glycoproteins from subtypes A
Study design and immunization schedule
In this study rabbits were immunized in one of five schedules in order to provide a direct comparison as to the relative immunogenicities of homologous vs. heterologous prime-boost vaccinations. These approaches (summarized in Fig. 1) utilize HIV-1 JR-FL gp120 as a model antigen delivered as either a DNA vaccine or a recombinant protein vaccine.
Groups of NZW rabbits were immunized with one of the following regimens: (1) five JR-FL gp120 DNA immunizations; (2) five JR-FL gp120 protein
Discussion
Recent studies have suggested that a heterologous prime-boost vaccination approach in which the same antigen is delivered sequentially by different types of vaccines was more effective in eliciting higher immune responses than the homologous prime-boost using same type of vaccines [14]. In the current study we have built upon previous work [15], [16] in evaluating humoral responses generated using HIV-1 gp120 antigen as a model antigen delivered by different prime-boost regimens. A more
Acknowledgements
This work was supported in part by US NIH/NIAID grants AI065250, AI082274, & AI082676 and grant Number 5 P30 DK32520 from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors would like to acknowledge the generous gifts of mAbs from Drs. Dennis Burton (b12), James Robinson (17b) and Susan Zolla-Pazner (447-52D). Authors would like to thank Dr. Jill M. Grimes Serrano for critical reading and editing of the manuscript.
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