Abstract
Chickenpox cases in the US drop by 80%
Novel immunotherapy for breast, ovarian and prostate cancer successfully completes Phase 1
Important progress for Inovio’s universal influenza vaccine
Vaccine against ricin exposure successful in phase 1B
BCG could help reverse Type 1 Diabetes
HPV vaccine: effective, when given early
First vaccine for visceral leishmaniasis starts human testing
CDC prepares vaccine for new swine flu strain
Chickenpox cases in the US drop by 80%
The Centers for Disease Control and Prevention (CDC) reported a drop in varicella incidence (chickenpox) of almost 80% between 2000 and 2010.
A single dose of varicella vaccine was first recommended for use in the US in 1996. Since 2006, a second routine dose has been recommended. Children get the first dose between 12 and 15 months of age, and the second dose between 4 and 6 years of age, or at least three months after the first dose. Teenagers and adults who have not had chickenpox or the chickenpox vaccine are recommended to also get two vaccine doses at least four weeks apart.
According to a recent CDC report1 national surveillance has continuously improved since 1996. The number of states with adequate chickenpox reporting systems jumped from 12 to 31 between 2000 and 2010. In these 31 states, chickenpox dropped from 43 cases per 100,000 population in 2000 to nine cases per 100,000 in 2010 (79%). The report also shows that in the four years after the two-dose vaccine was introduced for children in 2006, cases of chickenpox declined about 70%, with the greatest declines being observed among children aged 5 to 9 years of age. As two-dose vaccination increases, the CDC expects to see further declines in chickenpox.
While most cases are mild, lasting five to ten days, some people become seriously ill. Symptoms of this common infectious disease include an itchy blister-like rash, tiredness, headache and fever. Adults typically become sicker than children.
Novel immunotherapy for breast, ovarian and prostate cancer successfully completes phase 1
Recently, the Canadian clinical stage vaccine company Immunovaccine Inc. published positive results from a phase 1 clinical trial of its DPX-0907 cancer vaccine in the Journal of Translational Medicine.1 The published paper details new findings on specific polyfunctional T-cell responses generated by DPX-0907, as well as previously announced positive safety and immune response findings from the study.
DPX-0907 is a unique multi-targeted therapeutic vaccine designed to train the immune system, in particular T-cells, to recognize and destroy cancer cells. The vaccine combines seven tumor-associated antigens (TAAs)—all of them naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells—with Immunovaccine’s novel DepoVax adjuvanting delivery platform. DepoVax creates a depot effect upon vaccination, resulting in prolonged presentation of antigens and adjuvant to the immune system. Incorporating multiple target antigens allows the vaccine to attack cancer cells through multiple avenues and potentially reduces the chance for cancer cells to escape the therapy.
The open-label, dose-escalation phase 1 study, designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients, included 23 subjects (3 breast cancer, 7 ovarian cancer, 13 prostate cancer) in five centers in the US. Patients were divided into two dose/volume cohorts (0.25 or 1 mL doses) and received three injections of the active immunotherapy three weeks apart. Safety was assessed in eleven patients in the low-dose group and eleven in the high-dose group, after one of the ovarian cancer patients in the high-dose group discontinued the study, leaving a total of 22 patients with eleven patients in each of the dosage groups. Immunogenicity results are based on an analyis of nine evaluable patients in the low-dose group and nine evaluable patients in the high-dose group. DPX-0907 was generally well tolerated and considered safe at both dose levels. Furthermore, the study demonstrated antigen-specific CD8+ T-cell responses following vaccination. Of the trial’s evaluable cancer patients, 61% (11/18) showed the desired targeted T-cell responses against one or more of the seven TAAs contained in the vaccine. This number was even higher (89%, or 8/9) when looking only at patients with breast or ovarian cancer. Immune monitoring also demonstrated the generation of antigen-specific T-cell memory with the ability to secrete multiple Type 1 cytokines.
Of the study’s immune responders, 73% generated a response following the first vaccination suggesting favorable immune induction potential for DPX-0907, and 64% maintained a persistent response at one month following the third dose.
While the focus of the study was on evaluating antigen-specific CD8+ T-cells, CD4 responses against a T-helper peptide included in the vaccine were also detected. The CD4 responses correlated with antigen-specific CD8+ T cell responses in the same assay, supporting the hypothesis that the CD4 responses may have facilitated the generation of the specific CD8+ T cells observed.
“We believe that the breadth of positive data generated by this very first clinical study of DPX-0907 and the DepoVax technology provides support for the potential therapeutic value of both the product and the platform. Importantly, the valuable information that we have learned from this study, in terms of safety, immune response and patient profile, provides Immunovaccine with critical insight into how best to proceed with the clinical development of this novel approach to cancer immunotherapy,” said Dr Marc Mansour, Immunovaccine’s chief scientific officer.
Reference
1. Berinstein NL, et al. J Transl Med 2012; 10:156.
Important progress for Inovio’s universal influenza vaccine
Inovio Pharmaceuticals recently announced positive interim data from a phase 1 trial of its SynCon universal H1N1 influenza vaccine. The vaccine generated protective hemagglutination inhibition (HAI) titers against some of the most prevalent strains of the past 100 years.
Inovios‘ SynCon vaccines are designed to provide universal cross-strain protection against known as well as newly emergent unmatched strains of pathogens such as influenza. The two synthetic H1N1 hemagglutinin (HA) plasmids, tested in the current phase 1 study, incorporate sequence information from multiple divergent strains. The vaccines are not matched to any of the historical flu strains.
Healthy adults received these plasmids up to three times via intradermal electroporation, and the vaccine was well tolerated. Blood samples of vaccinated subjects were exposed to each of the nine key H1N1 viruses in circulation over the last 100 years: eight were H1N1 strains used to formulate the seasonal vaccines of the last 25 years; one was the H1N1 strain that caused the 1918 Spanish flu. These unmatched influenza strains were used to assess the generation of HAI titers meeting or exceeding 1:40. HAI titer of 1:20 is regarded as a positive vaccine response, while 1:40 is considered a protective immune response against influenza. The interim data analysis showed that a significant percentage of subjects immunized with Inovio’s SynCon vaccine had a HAI titer ≥ 1:40 against each of the nine H1N1 strains tested, demonstrating the vaccine’s broad cross-reactive coverage. A control group was immunized with the seasonal TIV (trivalent influenza vaccine) matched to the current H1N1 seasonal flu strain (A/California/07/09). Compared to the control group, subjects immunized with Inovio’s vaccine generated a higher or similar percentage of positive HAI titer responders against all of the strains except for A/California/07/09. As anticipated, the TIV recipients generated the best HAI titers against the matched strain, but did not generate vaccine-induced response rates against the unmatched strains.
The achievement of protective titers against multiple unmatched strains represents a major step towards Inovio’s ultimate goal to develop a universal influenza vaccine to protect against known and newly emerging strains of influenza.
“With respect to influenza, our ultimate objective is to develop a universal vaccine capable of providing years of true preemptive protection across subtypes and strains,” said Dr J. Joseph Kim, Inovio’s President and CEO. “This is a challenging goal, but this proof-of-principle H1N1 data demonstrates the potential of our SynCon approach to generate cross-protective HAI titers against multiple unmatched influenza strains. These results are an important addition to our previously reported H5N1 phase I data and a validating achievement on our ongoing effort to develop a safe vaccine that provides immunity against the ever-changing influenza virus.”
Vaccine against ricin exposure successful in phase 1B
The development stage biopharmaceutical company Soligenix recently announced positive results from a phase 1B clinical trial of an aluminum hydroxide (Alum) adjuvanted formulation of RiVax, a vaccine designed to protect against Ricin toxin exposure.
Ricin toxin, classified by the CDC as a Category B biological agent, is a protein consisting of A and B subunits that can be extracted from the beans of the castor plant, Ricinus communis. Once one is exposed to lethal doses of ricin, death is irreversible after four hours and takes three to five days to kill an individual. Currently there are no FDA approved therapeutics of vaccines that can protect against ricin toxin exposure or reverse its effects once exposed.
Soligenix is a world leader with RiVax in the field of ricin toxin vaccine research. The recombinant subunit vaccine, developed to protect against exposure to ricin toxin, contains a genetically altered version of ricin A chain with two mutations that inactivate the inherent toxicity of the ricin molecule.
The phase 1b trial, conducted by investigators at the University of Texas Southwestern Medical Center (UTSW), aimed to evaluate the long-term safety and immunogenicity of escalating doses of RiVax up to one year after primary vaccination. The vaccine was administered by intramuscular injection to healthy volunteers at 0, 6 weeks, and 6 months in doses of 10 and 100 µg. RiVax was well tolerated in all individuals with only mild side effects. At the peak of antibody titers two weeks after the third vaccination, all of the subjects had developed neutralizing antibodies against ricin toxin. When comparing peak antibody titers obtained in the phase 1b trial to that of the prior phase 1a trial which used an Alum-free formulation of RiVax, all subjects in the low dose group (10 µg) of the phase 1b trial developed neutralizing antibodies with the Alum formulation of RiVax compared to only one of five subjects in the low dose group of the Alum-free vaccine. In the high dose group (100 µg), peak neutralizing titers were 4-fold higher with the Alum formulation as compared to the Alum-free formulation, with total antibody anti-Ricin titers 17-fold higher. All vaccinees in the phase 1b trial were seropositive at nine months after the first vaccination, with 60% remaining positive at one year.
Results of the phase 1b study have recently been published in the journal Clinical and Vaccine Immunology.1 Results of the prior Phase 1a trial of RiVax were published in the journal Proceedings of the National Academy of Science of the USA.2
“These positive results indicate a route forward for the further development of the vaccine in larger and more definitive trials in humans and to provide the additional correlates of protective immunity in pivotal animal studies,” said Dr Robert N. Brey, Chief Scientific Officer of Soligenix. “The phase 1b results demonstrate that well-characterized adjuvants can improve the performance of highly purified subunit antigens such as the one contained in RiVax. The next steps for the development of RiVax will include the evaluation of secondary adjuvants to enhance the induction of neutralizing antibodies in fewer doses and the employment of our ThermoVax technology to stabilize the ingredients of the vaccine for long-term storage at ambient temperature conditions.”
References
1. Vitetta ES, et al. Clin Vaccine Immunol 2012; 19:1697-9.
2. Vitetta ES, et al. Proc Natl Acad Sci U S A 2006;103:2268-73.
BCG could help reverse Type 1 Diabetes
According to a new study, the tuberculosis vaccine bacillus Calmette-Guérin (BCG), which has been in use for 90 years, may help reverse Type 1 diabetes (T1D) and reduce the life-long need for insulin injections.
About three million Americans suffer from T1D, a condition usually diagnosed in childhood. In order to control their levels of blood sugar, T1D patients must inject insulin daily. Their bodies do not produce the hormone as a result of an errant immune system that destroys insulin-producing β-cells in the pancreas. No targeted immunotherapies yet exist to reverse T1D in humans despite some promising clinical data. However, in a rodent model of T1D, BCG was shown to reverse disease by restoring insulin secretion.
The result seen in animals has been confirmed in a small human study, published in the journal PLoS One.1 Researchers from Harvard University administered two doses of BCG to three adults with long-term T1D, with three T1D patients serving as placebo controls. Subjects were followed for 20 weeks. Two of the three vaccinated patients had signs of renewed insulin production. Specifically, BCG stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn kills pathogenic T cells and restores pancreatic β-cell function through regeneration.
“These patients have been told their pancreases were dead,” said study lead author Dr Denise Faustman, director of Harvard-affiliated Massachusetts General Hospital’s immunobiology laboratory. “We can take those people, give them a very low dose twice, and see their pancreases kick in and start to make small amounts of insulin.“
Dr Faustman and her colleagues at Massachusetts General in Boston are working to continue clinical testing of the vaccine. But there is no interest from major pharmaceutical companies in developing the vaccine as a possible cure for T1D, according to Dr Faustman. One obvious reason is that there is not an attractive commercial opportunity with an inexpensive generic vaccine such as BCG. The researchers are trying to raise the money to pay for larger clinical trials. So far, the Faustman lab has received from private donors $11M of the $25M needed to pay for the next stage of testing.
BCG, a weakened form of the tuberculosis bacteria, is approved by the FDA as an injectable vaccine for tuberculosis, but is not generally recommended for use in the US. The vaccine also is approved for intravesical use for bladder cancer. In Italy, the vaccine‘s ability to raise levels of cell-killing TNF is being studied as a way to treat multiple sclerosis (MS). Researchers found that the vaccine may prevent progression of brain lesions in patients with advanced stages of MS.
Reference
1. Faustman DL, et al. PLoS One. 2012; 7:e41756
HPV vaccine: effective, when given early
The human papilloma virus (HPV) vaccine can decrease prevalence of vaccine-type HPV strains in vaccinated women, and there is evidence of heard protection in unvaccinated individuals. To be most effective it is important that the vaccine is given before girls and boys become sexually active.
One study, published recently in the journal Pediatrics,1 showed a significant decrease in the prevalence of vaccine-type HPV among vaccinated young women and evidence of herd protection in unvaccinated women.
Researchers from the Cincinnati Children’s Hospital Medical Center in Ohio compared prevalence rates of HPV in young women before and after HPV vaccine introduction. Females aged 13–26 years who had had sexual contact were recruited for a pre-vaccination study in 2006–7 (368 women; 0% vaccinated) and a post-vaccination study in 2009–10 (409 women; 59% vaccinated). Participants were tested for cervicovaginal HPV DNA and completed a questionnaire. Propensity score weighting was used to balance differences in covariates between the two surveillance studies.
The researchers found that among all participants (mean age, 19 years), the prevalence rate for vaccine-type HPV decreased significantly from 31.7 to 13.4%. The decrease was seen among vaccinated (31.8 to 9.9%), but also among the unvaccinated (30.2 to 15.4%) post-surveillance study participants. For vaccinated post-surveillance study participants, there was a significant increase in nonvaccine-type HPV (60.7 to 75.9%).
The authors conclude that four years after licensing of the quadrivalent HPV vaccine, a substantial decrease in vaccine-type HPV prevalence and evidence of herd protection were observed. The increase in nonvaccine-type HPV in vaccinated participants should be interpreted with caution but warrants further study.
Another recent study found that more than half of girls 13 years and older already have an HPV infection. The study, recently published in the journal Archives of Pediatric and Adolescent Medicine,2 tested 259 young women aged 13–21 for HPV during clinic visits for their first vaccine dose. Among 190 who were sexually active, 70% were already infected. Even girls who had sexual contact without intercourse were at risk, with 11% testing positive for the virus.
The three-dose vaccine, proven to reduce the risk of HPV infection, is recommended for 11 and 12 year old girls, according to the CDC. But some doctors delay the shots, thinking pre-teens have a low risk for sexually transmitted infection.
“It really is important for physicians to offer the vaccine as recommended to girls that are 11 and 12 years old,” said Dr Lea Widdice, assistant professor of adolescent medicine at Cincinnati Children’s Hospital Medical Center and lead author of the study. “The vaccine is very safe and highly effective, but it works best if we can give it to girls and boys before they’re sexually active.”
Dr Widdice warns that the vaccine can only prevent the infection but cannot cure someone who is already HPV-positive. Thus, early vaccination is key to reduce HPV infection, which beyond cervical cancer is also linked to genital warts and cancers of the vulva, vagina, penis, anus and throat.
References
1. Kahn JA. Pediatrics 2012; 130:e249-56.
2. Arch Pediatr Adolesc Med 2012; 166:774-6.
First vaccine for visceral leishmaniasis starts human testing
Human trials of the first vaccine against leishmaniasis, developed by the Infectious Disease Research Institute (IDRI) in Seattle, have started. After more than 20 years of research, the non-profit organization is testing its vaccine in three dozen volunteers in Tacoma, Washington. The vaccine’s safety will also be tested in India later this year. If found safe, the vaccine will be studied in a larger popoluation in India to determine its efficacy.
The parasite Leishmania is spread to humans by sand flies. It is estimated that more than 12 million people worldwide are infected with Leishmania. India, Bangladesh and Brazil are among the countries where the virulent version of the pathogen is most prevalent. But the WHO says the disease is spreading as a result of deforestation, irrigation and dam building that expand habitat for sand flies. Climate change may also be a factor. Leishmaniasis is still rare in the US, but locally contracted cases have been reported in south-central Texas and more recently in the northern part of the state. The disease comes in many forms, the most common one being a cutaneous infection resulting in painful skin lesions that are slow to heal and leave disfiguring scars. In the most dangerous manifestation, called visceral leishmaniasis (or black fever), parasites attack the liver, spleen and bone marrow. Victims suffer from anemia, fever and a weakened immune system that leaves them vulnerable to other infections. Pigments from ruptured blood cells can turn the skin dark, hence the name “black fever.”
Treatments for leishmaniasis exist, but most have serious side effects or are not accessible to the world’s poor. Drug resistance is also rising. The Bill & Melinda Gates Foundation is funding the work on IDRI’s new vaccine, which is designed to fight the most serious form of the disease, visceral leishmaniasis. Dr Steve Reed, founder of IDRI, is optimistic the new vaccine could be ready for market in five years.
Researchers at IDRI are seeking cures for several neglected diseases, but leishmaniasis is the one that they have worked on longest. To manufacture the vaccine for clinical trials in Asia and for commercial distribution, IDRI partnered with an Indian pharmaceutical company. India has more leishmaniasis cases than any other country, and it is important to keep the cost of the vaccine low so it can reach the people in need.
CDC prepares vaccine for new swine flu strain
The emergence of a new strain of “swine flu“ has prompted the CDC to prepare a H3N2 candidate vaccine, which will be tested in the clinic this year. Up to early August, around 30 cases of influenza caused by this new strain had been identified, but the CDC is making sure it is prepared should the H3N2 strain become more widespread.
What concerns the CDC about this particular virus is that is contains an element seen in the pandemic 2009 swine flu strain H1N1, which may make it more likely for the virus to spread from person to person.
In a press conference in early August 2012, Dr Joseph Bresee from the CDC`s influenza divison explained that all reported cases were infected with strains of H3N2 that contained the matrix (m) gene from the influenza A H1N1 pandemic virus. “This ‘m’ gene may confer increased transmissibility to and among humans, compared with other variant influenza viruses“, he said.
Furthermore, the virus appears to have become more active recently. First detected in humans in July 2011, a total of 29 cases had been detected by early August. Looking at the period from July 12 to September 6, 2012, a total of 296 infections with influenza A (H3N2) variant (H3N2v) virus had been reported from ten states. For more details and updates visit the CDC’s website.1 The vast majority of cases seem to have occurred after prolonged swine exposure, though instances of likely human-to-human transmission have been identified in three cases in 2011. Sustained person-to-person transmission of the virus has not yet been documented.
There is not yet a cause for alarm, according to the CDC. “Because influenza viruses are always evolving, we will watch closely for signs that the virus has gained capacity for efficient and sustained human-to human transmission,” said Dr Bresee. “Thus far we have not seen this type of transmission and therefore are not seeing features consistent with an influenza pandemic.”