A Focus on Vaccination Strategies

Vaccination has proven to be one of the most effective public health strategies for the control of infectious disease. Vaccines against polio, measles, mumps, diphtheria (to name just a few) have considerably improved childhood survival rates and overall longevity and health of the population. Furthermore, vaccination has successfully eradicated the scourges of both small pox and rinderpest (a disease that was a major problem in domestic cattle). While the success of vaccines is clear, there are still many diseases for which adequate vaccines are not available. A key problem is that most vaccines operate by inducing humoral responses, yet many pathogens are able to evade antibody responses. For example, some pathogens have relatively high mutation rates that enable them to escape effective antibody responses. Other pathogens are insensitive to antibodies and can only be controlled by cellular immune responses. But the development of vaccines that elicit durable and effective cellular immunity remains elusive, especially with respect to mucosal infections. In the current issue of Viral Immunology, several papers are presented that specifically discuss issues related to vaccine design and development. These include articles on both vaccines against viral infections and the use of viral vectors to elicit responses to other diseases, such as cancer. The data are encouraging.

Outbreaks of the highly pathogenic influenza H5N1 virus in both poultry and humans represent a major clinical concern. The virus has the potential to cause a major pandemic in humans that could lead to very high mortality across the globe. Park et al. assessed the efficacy of a baculovirus expression-based vaccine based on the H5N1 hemagglutinin (HA) protein. Immunized chickens and ducks were protected against lethal challenge with an H5N1 virus in an antigen dose-dependent manner. Importantly, since the vaccine specifically elicited anti-HA responses, baculovirus-HA vaccinated poultry can be readily differentiated from infected poultry by a neuraminidase inhibition assay, an important concern for the poultry industry. Adeno-associated viruses (AAVs) are established vectors for gene therapy and for the delivery of antigens in a vaccine context. Manzano-Szalai et al. evaluated the immunogenicity and safety of an adenovirus-associated virus like particle (AAVLP) that displays a B-cell peptide epitope from ovalbumin (OVA) as a model antigen. Mice infected with the vector developed similar titers of OVA-specific IgG1 as mice immunized with native OVA protein. The authors conclude that AAVLPs that display of B-cell epitope peptides on their surface are promising vaccine candidates. Despite a checkered history, DNA vaccination remains a promising approach for vaccine development. Zhang et al. employed this technology to design a vaccine against hepatitis B virus (HBV). To enhance the immunogenicity of the vaccines, the authors introduced the interleukin (IL)-21 gene into a DNA vaccine that expresses an HBV antigen. Vaccination of normal and HBV transgenic mice induced comparable levels of anti-HBV antibody and HBV-specific CD8+ T-cells demonstrating the immunogenicity of the vaccine and the capacity to break immune tolerance in HBV transgenic mice. However, the presence of the IL-21 gene did not significantly strengthen the immune response over that induced by a vaccine that did not contain the IL-21 gene.

Also on the vaccination frontier, Li et al. analyzed the neutralization domains (residues 221–239) of the rubella virus E1 neutralization epitope. Single amino acid substitutions in this region revealed that the replacement of amino acids R237 or H238 with charged amino acids abolished antibody-binding activity. The authors conclude that R237 and H238 are key amino acids in the rubella virus E1 neutralization epitope and are, therefore, important vaccine targets. Antibodies also play an important role in protection against human papillomavirus (HPV) and assays to measure HPV seropositivity have become increasingly important since HPV vaccines have become available worldwide. Therefore, da Silveira Gonçalves et al. compared enzyme-linked immunosorbent assay and polymerase chain reaction (PCR) analyses of HPV positivity and anti-HPV-VLP (the basis of the HPV vaccine) in 50 female patients between 18 and 35 years of age. Their data show that the assay data correlate very well with the presence of HPV16/18, as detected by PCR. The final vaccine paper in this issue addresses a novel vaccination approach using Lactococcus lactis that expresses HPV-16 E7 protein on its surface. Rangel-Colmenero et al. show that intranasal vaccination of mice with the L. lactis (Ll) vaccine in combination with an adenovirus-calreticulin/E7 vaccine induced approximately 80% tumor suppression compared to control mice. The authors conclude that immunization with Ll-E7 enhances the adenovirus-calreticulin/E7-mediated antitumor effect and offers an advantage over repeated applications of adenovirus-calreticulin/E7 by maintaining the effectiveness of the three-dose application of adenovirus-calreticulin/E7, but avoiding the high systemic toxicities associated with repeat treatments. Taken together, the vaccine-focused papers in this issue considerably advance our understanding of the efficacy of different vaccine strategies and specific vaccine targets. While there is still clearly much more to be learned, these and other studies are forming a foundation for future vaccine successes.

Two other papers in this issue of Viral Immunology address the host response to viral infection. Rizzo et al. show that HLA-C and KIR genotypes are risk markers for HPV infection and associated cervical lesion evolution. And Zhang et al. analyze the dynamics of human immunodeficiency virus (HIV)-1 DNA during the first year of infection to show that disease progression may be related to the body's ability to control HIV-1 during the early stages of infection.

I would like to thank all of the authors for their outstanding contributions to this issue of Viral Immunology and to all of the reviewers who assisted with the peer review process.