Host Responses from Innate to Adaptive Immunity after Vaccination: Molecular and Cellular Events

Sang-Moo Kang,Richard W. Compans 한국분자세포생물학회 2009 Molecules and cells Vol.27 No.1

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.

Influenza M1 VLPs containing neuraminidase induce heterosubtypic cross-protection

Quan, F.S.,Kim, M.C.,Lee, B.J.,Song, J.M.,Compans, R.W.,Kang, S.M. Academic Press 2012 Virology Vol.430 No.2

Influenza virus like particles (VLPs) containing hemagglutinin were previously demonstrated to induce protection against the homologous strains. However, little information is available on the protective role of neuraminidase (NA), the second major glycoprotein. In this study, we developed VLPs (NA VLPs) containing NA and M1 derived from A/PR/8/34 (H1N1) influenza virus, and investigated their ability to induce protective immunity. Intranasal immunization with NA VLPs induced serum antibody responses to H1N1 and H3N2 influenza A viruses as well as significant neuraminidase inhibition activity. Importantly, mice immunized with NA VLPs were 100% protected against lethal infection by the homologous A/PR/8/34 (H1N1) as well as heterosubtypic A/Philippines/82 (H3N2) virus, although body weight loss was observed after lethal challenge with heterosubtypic H3N2 virus. The present study therefore provides evidence that influenza VLPs containing M1 and NA are capable of inducing immunity to homologous as well as antigenically distinct influenza A virus strains.

Proteomic Characterization of Influenza H5N1 Virus-like Particles and Their Protective Immunogenicity

Song, Jae-Min,Choi, Chi-Won,Kwon, Sang-Oh,Compans, Richard. W.,Kang, Sang-Moo,Kim, Seung Il American Chemical Society 2011 JOURNAL OF PROTEOME RESEARCH Vol.10 No.8

<P>Recombinant virus-like particles (VLPs) have been shown to induce protective immunity. Despite their potential significance as promising vaccine candidates, the protein composition of VLPs produced in insect cells has not been well characterized. Here we report a proteomic analysis of influenza VLPs containing hemagglutinin (HA) and matrix M1 proteins from a human isolate of avian influenza H5N1 virus (H5 VLPs) produced in insect cells using the recombinant baculovirus expression system. Comprehensive proteomic analysis of purified H5 VLPs identified viral proteins and 37 additional host-derived proteins, many of which are known to be present in other enveloped viruses. Proteins involved in different cellular structures and functions were found to be present in H5 VLPs including those from the cytoskeleton, translation, chaperone, and metabolism. Immunization with purified H5 VLPs induced protective immunity, which was comparable to the inactivated whole virus containing all viral components. Unpurified H5 VLPs containing excess amounts of noninfluenza soluble proteins also conferred 100% protection against lethal challenge although lower immune responses were induced. These results provide important implications consistent with the idea that VLP production in insect cells may involve similar cellular machinery as other RNA enveloped viruses during synthesis, assembly, trafficking, and budding processes.</P><P>Virus-like particles (VLPs) have been shown to induce protective immunity, indicating a new platform of promising vaccine candidates. We have performed comprehensive proteomic analysis of influenza H5 pandemic potential VLP vaccines. We identified influenza viral proteins as well as host- and vector-derived proteins. The results suggest that VLP production may involve similar cellular machinery as other enveloped viruses during synthesis, assembly, trafficking, and budding processes.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jprobs/2011/jprobs.2011.10.issue-8/pr200086v/production/images/medium/pr-2011-00086v_0004.gif'></P>

Virus-like Particles Containing Multiple M2 Extracellular Domains Confer Improved Cross-protection Against Various Subtypes of Influenza Virus

Kim, Min-Chul,Song, Jae-Min,Eunju, O,Kwon, Young-Man,Lee, Youn-Jeong,Compans, Richard W,Kang, Sang-Moo Elsevier Science B.V., Amsterdam 2013 Molecular therapy Vol.21 No.2

Improved protection against avian influenza H5N1 virus by a single vaccination with virus-like particles in skin using microneedles

Song, J.M.,Kim, Y.C.,Barlow, P.G.,Hossain, M.J.,Park, K.M.,Donis, R.O.,Prausnitz, M.R.,Compans, R.W.,Kang, S.M. Elsevier/North-Holland 2010 Antiviral research Vol.88 No.2

To develop a more effective vaccination method against H5N1 virus, we investigated the immunogenicity and protective efficacy after skin vaccination using microneedles coated with influenza virus-like particles containing hemagglutinin derived from A/Vietnam/1203/04 H5N1 virus (H5 VLPs). A single microneedle vaccination of mice with H5 VLPs induced increased levels of antibodies and provided complete protection against lethal challenge without apparent disease symptoms. In contrast, intramuscular injection with the same vaccine dose showed low levels of antibodies and provided only partial protection accompanied by severe body weight loss. Post-challenge analysis suggested that improved protection was associated with lower lung viral titers and enhanced generation of recall antibody secreting cells by microneedle vaccination. Thus, this study provides evidence that skin delivery of H5 VLP vaccines using microneedles designed for self-administration induces improved protection compared to conventional intramuscular immunization.

Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection

Kim, M.C.,Lee, J.S.,Kwon, Y.M.,O, E.,Lee, Y.J.,Choi, J.G.,Wang, B.Z.,Compans, R.W.,Kang, S.M. Elsevier/North-Holland 2013 Antiviral research Vol.99 No.3

The influenza M2 ectodomain (M2e) is poorly immunogenic and has some amino acid changes among isolates from different host species. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Immunization of mice with M2e5x VLPs induced protective antibodies cross-reactive to antigenically different influenza A viruses and conferred cross protection. Anti-M2e antibodies induced by heterologous M2e5x VLPs showed a wider range of cross reactivity to influenza A viruses at higher levels than those by live virus infection, homologous M2e VLPs, or M2e monoclonal antibody 14C2. Fc receptors were found to be important for mediating protection by immune sera from M2e5x VLP vaccination. The present study provides evidence that heterologous recombinant M2e5x VLPs can be more effective in inducing protective M2e immunity than natural virus infection and further supports an approach for developing an effective universal influenza vaccine.

Protection against lethal challenge by Ebola virus-like particles produced in insect cells

Sun, Y.,Carrion, R.,Ye, L.,Wen, Z.,Ro, Y.T.,Brasky, K.,Ticer, A.E.,Schwegler, E.E.,Patterson, J.L.,Compans, R.W.,Yang, C. Academic Press 2009 Virology Vol.383 No.1

Ebola virus-like particles (VLPs) were produced in insect cells using a recombinant baculovirus expression system and their efficacy for protection against Ebola virus infection was investigated. Two immunizations with 50 μg Ebola VLPs (high dose) induced a high level of antibodies against Ebola GP that exhibited strong neutralizing activity against GP-mediated virus infection and conferred complete protection of vaccinated mice against lethal challenge by a high dose of mouse-adapted Ebola virus. In contrast, two immunizations with 10 μg Ebola VLPs (low dose) induced 5-fold lower levels of antibodies against GP and these mice were not protected against lethal Ebola virus challenge, similar to control mice that were immunized with 50 μg SIV Gag VLPs. However, the antibody responses against GP were boosted significantly after a third immunization with 10 μg Ebola VLPs to similar levels as those induced by two immunizations with 50 μg Ebola VLPs, and vaccinated mice were also effectively protected against lethal Ebola virus challenge. Furthermore, serum viremia levels in protected mice were either below the level of detection or significantly lower compared to the viremia levels in control mice. These results show that effective protection can be achieved by immunization with Ebola VLPs produced in insect cells, which give high production yields, and lend further support to their development as an effective vaccine strategy against Ebola virus.

Protective immunity against H5N1 influenza virus by a single dose vaccination with virus-like particles

Song, J.M.,Hossain, J.,Yoo, D.G.,Lipatov, A.S.,Davis, C.T.,Quan, F.S.,Chen, L.M.,Hogan, R.J.,Donis, R.O.,Compans, R.W.,Kang, S.M. Academic Press 2010 Virology Vol.405 No.1

We generated influenza virus-like particles (VLPs) containing the wild type (WT) H5 hemagglutinin (HA) from A/Viet Nam/1203/04 virus or a mutant H5 HA with a deletion of the multibasic cleavage motif. VLPs containing mutant H5 HA were found to be as immunogenic as VLPs containing WT HA. A single intramuscular vaccination with either type of H5 VLPs provided complete protection against lethal challenge. In contrast, the recombinant H5 HA vaccine was less immunogenic and vaccination even with a 5 fold higher dose did not induce protective immunity. VLP vaccines were superior to the recombinant HA in inducing T helper type 1 immune responses, hemagglutination inhibition titers, and antibody secreting cells, which significantly contribute to inducing protective immunity after a single dose vaccination. This study provides insights into the potential mechanisms of improved immunogenicity by H5 VLP vaccines as an approach to improve the protective efficacy against potential pandemic viruses.