Papers of the Month – 2012

December, 2012

Vaccine.  2012. Dec 19 [Epub ahead of print].

Christopher S. Ambrose and Xionghua Wu

Intranasal live attenuated influenza vaccine (LAIV) has potential for self-administration (SA) by adults and adolescents, which could save time and cost in mass vaccination settings. Participants in a study of LAIV in adults (n=4561) selected either SA or health care provider (HCP) administration and were followed for febrile illness during the influenza season. More LAIV recipients chose SA-LAIV (72%) than HCP-LAIV (28%). Overall, 97% of SA-LAIV and 98% of HCP-LAIV recipients had no problems with vaccine administration. Four of 13 study sites enrolled more than 50 subjects in both cohorts. Overall and for these 4 sites, illness incidence was similar with SA-LAIV and HCP-LAIV. Solicited reactogenicity events and adverse events through 7 days post vaccination were comparable for SA-LAIV and HCP-LAIV recipients; both groups exhibited increased runny nose, sore throat, and cough relative to placebo recipients. SA-LAIV and HCP-LAIV appeared similarly effective against influenza-like illness and had comparable safety profiles.

November, 2012

PLoS Negl Trop Dis.  2012. 6(10):e1876

Dennis L. Chao, Scott B. Halstead, M. Elizabeth Halloran, Ira M. Longini Jr.

Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the foreseeable future. With four interacting dengue serotypes, the development of an effective vaccine has been a challenge. Several dengue vaccine candidates are currently being tested in clinical trials. Before the widespread introduction of a new dengue vaccine, one n eeds to consider how best to use limited supplies of vaccine given the complex dengue transmission dynamics and the immunological interaction among the four dengue serotypes.

Methodology/Principle findings: We developed an individual-level (including both humans and mosquitoes), stochastic simulation model for dengue transmission and control in a semi-rural area in Thailand. We calibrated the model to dengue serotype-specific infection, illness and hospitalization data from Thailand. Our simulations show that a realistic roll-out plan, starting with young children then covering progressively older individuals in following seasons, could reduce local transmission of dengue to low levels. Simulations indicate that this strategy could avert about 7,700 uncomplicated dengue fever cases and 220 dengue hospitalizations per 100,000 people at risk over a ten-year period.

Conclusions/Signifigace: Vaccination will have an important role in controlling dengue. According to our modeling results, children should be prioritized to receive vaccine, but adults will also need to be vaccinated if one wants to reduce community-wide dengue transmission to low levels.

October, 2012

Journal of Virology.  2012.  Oct 17 [Epub ahead of print]

Anasuya Chattopadhyay, Eryu Wang, Robert Seymour, Scott C. Weaver, and John K. Rose.

While a large number of mosquito-transmitted alphaviruses are known to cause serious human diseases, there are no licensed vaccines that protect against alphavirus infections. The alphavirus chikungunya virus (CHIKV) has caused multiple recent outbreaks of chikungunya fever. This virus has the potential to cause a worldwide epidemic and has generated strong interest in development of a prophylactic CHIKV vaccine. We report here on the development of a potent experimental vaccine for CHIKV based on a chimeric vesicular stomatitis virus (VSV) expressing the entire CHIKV envelope polyprotein (E3-E2-6K-E1) in place of the VSV glycoprotein (G). These VSVΔG-CHIKV chimeras incorporated functional CHIKV glycoproteins into the viral envelope in place of VSV G. The chimeric viruses were attenuated for growth in tissue culture, but could be propagated to high titers without VSV G complementation. They also generated robust neutralizing antibody and cellular immune responses to CHIKV in mice after a single dose, and protected mice against CHIKV infection. VSVΔG-alphavirus chimeras could have general applicability as alphavirus vaccines.

September, 2012

Vaccine.  2012.  30:6054-6063

Venkata R. Duvvuri, Alex Marchand-Austin, Alireza Eshaghi, Samir N. Patel, Donald E. Low, Jonathan B. Gubbay.

An immuno-informatics study was conducted to determine possible pre-existing T cellular immunity to the recently emerged swine-origin triple reassortant H3N2 variant (S-OtrH3N2v-2011) which acquired the matrix gene of influenza A (H1N1)pdm09. Given the genetic origin of S-OtrH3N2v-2011, our study focused on the hemagglutinin (HA) and matrix1 (M1) proteins to identify common and conserved T cell epitopes. We compared HA CD4+ T cell epitopes of S-OtrH3N2v-2011 with seasonal H3N2 (1968–2011)-HA proteins. M1 CD4+ and CD8+ T cell epitopes of S-OtrH3N2v-2011 were compared with the M1 proteins of seasonal H1N1 (1977–2009) and A (H1N1)pdm09 (2009–2011) subtypes. The results revealed a high conservancy of epitopes localized particularly on HA2 and the entire M1 protein. The overall cross reactivity of predicted CD4+ T cell epitopes with previously experimentally defined (Immuno Epitope Database) CD4+ T epitopes of HA and M1 proteins was ~51%. CD8+ T cell cross-reactivity of ~74% was documented for M1 protein. Analysis suggests possible pre-existing CD4+ T cell immunity to S-OtrH3N2v-2011 in the human population.

August, 2012

PLoS One. 2012. 7(8):e40928

Simon H. Apte, Penny L Groves, Mariusz Skwarczynski, Yoshio Fujita, Chenghung Chang, Istvan Toth, Denise L Doolan.

Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP) vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4(+) and/or CD8(+) T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8(+) T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8(+) T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.

July, 2012

Nature Medicine. 2o12. Jul 15. [Epub ahead of print]

Q. Zhu, J. Talton, G. Zhang, T. Cunningham, Z. Wang, R.C. Waters, J. Kirk, B. Eppler, D.M. Klinman, Y. Sui, S. Gagnon, I.M. Belyakov, R.J. Mumper, and J. A. Berzofsky.

Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine’s destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.

June, 2012

J. Infect Dis. 2o12. Jun 4 [Epub ahead of print]

H.F. Tseng, M. Chi, N. Smith, S.M. Marcy, L.S. Sy, S. J. Jacobsen

Background: The benefit of vaccinating immunocompetent patients who have had shingles has not been examined. The study assessed the association between vaccination and the incidence of herpes zoster recurrence among persons with a recent episode of clinically diagnosed herpes zoster.

Methods: This is a matched cohort study in Kaiser Permanente Southern California. Study populations were immunocompetent elderly individuals ≥60 years old with a recent episode of herpes zoster. Incidence of recurrent herpes zoster was compared between the vaccinated and the unvaccinated matched cohorts.

Results: A total of 1036 vaccinated and 5180 unvaccinated members were included. On the basis of clinically confirmed cases, the incidence of recurrent herpes zoster among persons aged <70 years was 0.99 (95% confidence interval [CI], .02-5.54) and 2.20 (95% CI, 1.10-3.93) cases per 1000 person-years in the vaccinated and unvaccinated cohorts, respectively. The adjusted hazard ratio was 0.39 (95% CI, .05- 4.45) among persons aged <70 years and 1.05 (95% CI, .30-3.69) among persons aged ≥70 years.

Conclusions: The risk of herpes zoster recurrence following a recent initial episode is fairly low among immunocompetent adults, regardless of vaccination status. Such a low risk suggests that one should evaluate the necessity of immediately vaccinating immunocompetent patients who had a recent herpes zoster episode.

May, 2012

2012. Lancet Infect Dis. May 4. [Epub ahead of print]

Peter C Richmond, Helen S Marshall, Michael D Nissen, Qin Jiang, Kathrin U Jansen, Maria Garcés- Sánchez, Federico Martinón-Torres, Johannes Beeslaar, Leszek Szenborn, Jacek Wysocki, Joseph Eiden, Shannon L Harris, Thomas R Jones, John L Perez, on behalf of the 2001 Study Investigators

Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine.

This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at, number NCT00808028.

539 participants were enrolled and 511 received all three study vaccinations-116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg).

The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease.

April, 2012

J Virol. 2012 Mar 21 [Epub ahead of print] PMID: 22438541

Yo Han Jang, Young Ho Byun, Yoon Jae Lee, Yun Ha Lee, Kwang-Hee Lee, and Baik Lin Seong

The global transmission of the pandemic 2009 H1N1 influenza virus (pdmH1N1) among humans raised a serious concern for the potential emergence of genetic reassortant between the pdmH1N1 and other highly pathogenic influenza strains, especially the avian H5N1 influenza virus, geared to high mortality and rapid transmission. Vaccination remains the most rational and practical approach for the pandemic preparedness. We reported that the cold-adapted X-31 live attenuated pdmH1N1 vaccine (CApH1N1) elicits cross-reactive immunity to seasonal human influenza and avian H5 influenza viruses in the mouse model. The vaccination induced both systemic and mucosal antibodies with broad reactivity to seasonal and H5 strains including HPAI H5N1 and the avian H5N2 virus, providing complete protection against heterologous and hetero-subtypic lethal challenges by single immunization. The results further extend previous reports on the merit of using live attenuated influenza vaccine for cross-protection. While addressing to the biosecurity concerns associated with the lab-made mammalian-transmissible highly pathogenic H5N1 influenza viruses, the live vaccine shows its potential for mitigating the severity of infections with natural reassortants between pdmH1N1 and highly pathogenic H5 subtype viruses.

March, 2012

2012. PLoS Neglected Tropical Diseases 6(2): e1536.

Meng Ling Moi, Chang-Kweng Lim, Kaw Bing Chua, Tomohiko Takasaki, Ichiro Kurane

Dengue has become a major international public health concern in recent decades. There are four dengue virus serotypes. Recovery from infection with one serotype confers life-long protection to the homologous serotype but only partial protection to subsequent infection with other serotypes. Secondary infection with a serotype different from that in primary infection increases the risk of development of severe complications. Antibodies may play two competing roles during infection: virus neutralization that leads to protection and recovery, or infection- enhancement that may cause severe complications. Progress in vaccine development has been hampered by limited understanding on protective immunity against dengue virus infection. We report the neutralization activity and infection-enhancement activity in individuals with dengue in Malaysia. We show that infection-enhancement activity is present when neutralizing activity is absent or low, and cross-reactive neutralizing activity may be hampered by infection-enhancing activity. Conventional assays for titration of neutralizing antibody do not consider infection- enhancement activity. We used an alternative assay that determines the sum of neutralizing and infection-enhancement activity in sera from dengue patients. In addition to providing insights into antibody responses during infection, the alternative assay provides a new platform for the study of immune responses to vaccine.

February, 2012

2012 Science Translational Medicine Vol. 4, Issue 115. 115ra2

Colloca S, Barnes E, Folgori A, Ammendola V, Capone S, Cirillo A, Siani L, Naddeo M, Grazioli F, Esposito ML, Ambrosio M, Sparacino A, Bartiromo M, Meola A, Smith K, Kurioka A, O’Hara GA, Ewer KJ, Anagnostou N, Bliss C, Hill AV, Traboni C, Klenerman P, Cortese R, Nicosia A

In the quest for novel vaccines against chronic infectious diseases (ie: HIV, HCV, Tuberculosis) and cancer, the use of genes as vaccines (genetic vaccination) is a promising strategy because it efficiently stimulates both arms of the adaptive immune system. Adenoviruses are particularly efficient for the induction of CD8 effector and memory responses, a feature that is often missing when ‘traditional’ protein-based vaccines are used. However, most humans have anti-Ad5 neutralising antibodies that can impair the immunological potency of such a vector for human vaccine delivery. Other human Adenoviruses from rare serotypes are far less potent as vaccine vectors than Ad5 in mice and non-human primates, casting doubt on their potential efficacy in humans.

In the published work by Colloca et al., we have addressed the issue of lack of suitable Adenovirus by generating a ‘library’ of replication incompetent Adenovirus vectors isolated from chimpanzees (ChAd). Screening of this library by a combination of in vitro and in vivo approaches led to the identification of several candidates that are not neutralised by antibodies present in humans, have high immunological potency and can be produced in human cell lines approved by regulatory agencies. In a recent unpublished work, we have also shown that ChAd can protect from infection by different pathogens (RSV, Influenza, Ebola) in relevant animal models and can be considered suitable candidate carriers for vaccine delivery in humans. Consistently, two of the most potent ChAd vectors were selected for clinical studies as carriers for Malaria and Hepatitis C virus genetic vaccines where they proved to be safe and immunologically very potent.

In non human primates and in humans ChAd are extremely effective at priming immune responses that develop into long-term memory responses and are readily re-expanded in vivo by second encountering with the encoded pathogenic antigen. This feature can also be exploited by using ChAd vectors in heterologous prime/boost regimens with different ChAd vectors, or with different vaccine platforms (other vectors, naked DNA or proteins) as boosters.

In summary, ChAd vectors represent a platform technology that can be exploited for diverse vaccine strategies against infectious diseases and cancer.

January, 2012

Nature. 2012 Jan 4. doi: 10.1038/nature10766

Barouch DH, Liu J, Li H, Maxfield LF, Abbink P, Lynch DM, Iampietro MJ, Sanmiguel A, Seaman MS, Ferrari G, Forthal DN, Ourmanov I, Hirsch VM, Carville A, Mansfield KG, Stablein D, Pau MG, Schuitemaker H, Sadoff JC, Billings EM, Rao M, Robb ML, Kim JH, Marovich MA, Goudsmit J, Michael NL

Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization- resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/ poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post- infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.

The International Society for Vaccines is an organization that engages, supports, and sustains the professional goals of a diverse membership in all areas relevant to vaccines and immunotherapeutics.  The ISV is a global not-for-profit organization that aims to encourage, establish, and promote the development and use of vaccines to prevent and control infectious and non-infectious diseases in animals and humans.  /  ISV Annual Congress