Human Vaccines & Immunotherapeutics
ISSN: 2164-5515 (Print) 2164-554X (Online) Journal homepage: http://www.tandfonline.com/loi/khvi20
Human Vaccines & Immunotherapeutics: News To cite this article: (2014) Human Vaccines & Immunotherapeutics: News, Human Vaccines & Immunotherapeutics, 10:11, 3103-3106, DOI: 10.4161/21645515.2014.995038 To link to this article: http://dx.doi.org/10.4161/21645515.2014.995038
Published online: 27 Jan 2015.
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Article views: 17
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=khvi20 Download by: [206.214.12.105]
Date: 05 November 2015, At: 15:21
NEWS Human Vaccines & Immunotherapeutics 10:11, 3103--3106; November 2014; © 2014 Taylor & Francis Group, LLC
Human Vaccines & Immunotherapeutics: News
Downloaded by [206.214.12.105] at 15:21 05 November 2015
Ebola Vaccine Candidates are Tested in Humans It has been >6 months since the Ebola outbreak was declared. Countries hit hardest include Liberia, Guinea and Sierra Leone, but individual cases in the United States and Europe have also made the news. There are no available treatments or vaccine, but many pharmaceutical companies as well as the US National Institutes of Health (NIH) are determined to change that soon. The most advanced vaccine candidate, from GlaxoSmithKline (GSK), is being tested in a Phase 1 trial at the NIH campus in Bethesda (MD, USA). This candidate (cAd3-ZEBOV) employs a chimpanzee-derived replicationdefective adenovirus vector containing 2 Ebolavirus gene segments. The vaccine works by entering a cell, delivering DNA, and expressing Ebola protein for eliciting an immune response. cAd3-ZEBOV has elicited no major side effects so far in healthy volunteers. The trial began in September and should be completed by December. The same vaccine is also being tested in a clinical trial in Cambridge (UK), and the NIH plans to extend the studies
to Mali to assure that the vaccine is safe and effective. Phase 2 trials might begin in early 2015, and could include those at high-risk of Ebola, such as healthcare workers in the 3 most affected countries in West Africa. In a recent assessment, the World Health Organization (WHO) said that the expedited evaluation of trial-ready Ebola vaccines is a high priority, citing 2 promising vaccines: GSK`s cAd3-ZEBOV and rVSV-ZEBOV, which was conceived by the Public Health Agency of Canada in Winnipeg and is being developed by the US company NewLink Genetics. Clinical trials for rVSV-ZEBOV should start very soon. Other vaccines in development, yet not so far advanced, include candidates from Inovio Pharmaceuticals and Johnson & Johnson (J&J). Inovio recently announced that it will advance its DNA vaccine into a Phase 1 clinical trial in a collaboration with the international DNA vaccine manufacturer GeneOne Life Science Inc., Inovio’s Ebola vaccine candidate was designed using the company’s SynCon
technology to provide broad protective antibody and T-cell responses against multiple Ebolavirus strains. Preclinical testing showed that 100% of vaccinated guinea pigs and mice were protected from death after being exposed to Ebolavirus. Unlike non-vaccinated animals, vaccinated animals were also protected from weight loss, a measure of morbidity. Researchers found significant increases in neutralizing antibody titers and strong and broad levels of vaccine-induced T-cells, including killer T-cells, suggesting that this candidate could provide both preventive and treatment benefits. Inovio and GeneOne are conducting pre-IND activities and plan to start a clinical trial in the first half of 2015. J&J’s candidate vaccine recently received fast-track designation from the FDA. Clinical trials are expected to start early in 2015. Most of the experimental Ebola vaccines and therapies have not been tested in the clinic, thus it will be exciting to see if any of them will be successful in protecting humans from Ebola.
Novavax’ H7N9 Avian Influenza VLP Vaccine Positive in Phase 1/2 The clinical-stage biopharmaceutical company Novavax Inc., recently announced positive results from a Phase 1/2 clinical trial of its H7N9 avian influenza virus-like particle vaccine candidate (H7N9 VLP) formulated with their proprietary adjuvant Matrix-M. Novavax focuses on the discovery, development and commercialization of recombinant nanoparticle vaccines and adjuvants. In February 2011, the company was awarded a contract by BARDA valued at up to $179 million for the advanced development of recombinant influenza vaccine products and manufacturing capabilities for pandemic preparedness, and the current Phase 1/2 trial was conducted under this contract. The dose-ranging, randomized, observerblinded, placebo-controlled clinical trial
www.landesbioscience.com
included 610 healthy subjects to evaluate the safety and immunogenicity of the H7N9 VLP vaccine formulated with Matrix-M. The study was designed to determine the contribution of Matrix-M to potential antigen dose-sparing regimens. Study subjects received 2 doses of 15 mg of H7N9 VLP alone, or 3.8, 7.5 or 15 mg of H7N9 VLP in combination with either 25 or 50 mg of Matrix-M, or placebo. Serology was taken on Days 0, 21 and 42. The results showed that the H7N9 VLP vaccine candidate, with and without Matrix-M, was well tolerated and demonstrated a safety profile similar to the company’s prior experience with another saponin-based adjuvant. Matrix-M adjuvanted formulations demonstrated a clear immunogenicity benefit relative to unadjuvanted antigen, and a dose-response within the adjuvanted groups. Even the 3.8mg dose of
Human Vaccines & Immunotherapeutics
antigen with either tested dose of adjuvant gave immune responses significantly greater than 15mg dose without adjuvant, demonstrating a clear antigen dose-sparing effect. Geometric mean titers of hemagglutinationinhibiting antibody after 2 vaccine doses were comparable to those reported in prior studies with another saponin adjuvant when similar antigen and adjuvant doses were compared. Finally, strong neuraminidase inhibiting antibody responses were observed in adjuvanted vaccine groups. “This study represents the first clinical trial of Matrix-M with our VLPs. We are pleased with the performance of Matrix-M in this study, which increases our confidence in the value of this adjuvant and its future application in this and other recombinant nanoparticle products,” said Dr Stan Erck, President
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and CEO of Novavax. “Based on the data from this trial, we will discuss future clinical studies with our partner, BARDA. "Given the Matrix-M safety profile and dose response
observed in this study, we believe additional such studies are warranted to identify the best combination of antigen and adjuvant to achieve the greatest practical antigen dose
sparing, consistent with a strong immune response, thus potentially making available the maximum number of doses in a pandemic emergency.”
Downloaded by [206.214.12.105] at 15:21 05 November 2015
Half of all Flu Shots in the US are Provided by Pharmacists In the United States, pharmacies have established themselves as major providers of influenza vaccines in recent years. While public health officials and manufacturers welcome this development because it makes it easier for patients to get vaccinated, physicians have reservations about pharmacies delivering vaccines. In 1999, only 22 states allowed pharmacists to administer flu vaccines. A decade later, all 50 permitted the practice, after the outbreak of the H1N1 virus. Receiving the seasonal influenza vaccine in a pharmacy or drugstore is more convenient than going to the doctor’s office. There is no need for making an appointment, there are many possible locations to go to and longer opening hours, even on weekends. Customers can get immunized spontaneously while shopping.
Drugstores offering immunizations clearly lessens inconvenience as a barrier, but some doctors are concerned. They want to stay tuned into the health of their patients and keep track of who has received a vaccine. Moreover, appointments for flu vaccination often are also used to check up on any chronic conditions, such as diabetes, that affect their patients. “That relationship, knowing the patient, that is important,” Dr Robert Wergin, a family physician in Milford (NE, USA) and president-elect of the American Academy of Family Physicians told the Associated Press (AP). He added that many doctor’s offices have worked to become more convenient by offering same-day appointments for flu shots. Retailers on the other hand emphasize that their expansion into vaccinations is not meant
to replace a primary care doctor visit, and they offer to notify a customer`s doctor about a flu vaccination, if wanted by the patient. “It is all about providing our customers with access to affordable health care,” said Danit Marquardt, a Wal-Mart spokeswoman, to AP. Since 2000, the number of flu vaccines distributed in the US has nearly doubled to 134.5 million in the 2013-4 season. According to Dr Carolyn Bridges, Associate Director for adult immunizations for the US Centers for Disease Control and Prevention (CDC), it is unclear how much of this growth can be attributed to retail locations, but various studies have shown that easy access is a big factor for adults getting immunizations. Today, nearly half of all flu vaccines provided to adults are administered in non-medical settings such as drugstores.
Gut Microbiota Influence Immunity to Vaccination A new study found that mice treated with antibiotics to remove most of their intestinal bacteria or raised under sterile conditions have impaired antibody responses to seasonal influenza vaccination. These findings suggest that antibiotic treatment before or during vaccination could impair responses to certain vaccines in humans. Moreover, the results could also help explain why immunity induced by some vaccines varies in different parts of the world. Researcher from the Emory Vaccine Center in Atlanta (GA, USA) previously analyzed immune responses to influenza vaccination in humans, using the systems vaccinology‘ approach. They observed that the expression of the Toll-like-receptor (TLR) 5 gene a few days after vaccination correlated with strong antibody responses weeks later. TLR5 recognizes flagellin, the protein monomer that makes up the filament of bacterial
3104
flagellam found on nearly all motile bacteria. These findings led the researchers to further investigate the phenomenon in mice; results were recently reported in the journal Immunity (http://www.ncbi.nlm.nih. gov/pubm-ed/25220212). The research team vaccinated mice lacking TLR5 with trivalent seasonal influenza vaccine (TIV) and found reduced antibody titers and lower frequencies of plasma cells in these animals, suggesting a role for TLR5 in immunity to TIV. This was due to a failure to sense host microbiota. Antibody responses in germ-free or antibiotictreated mice were impaired, but could be restored by oral reconstitution with a flagellated, but not aflagellated, strain of E. coli. TLR5-mediated sensing of flagellin promoted plasma cell differentiation directly and by stimulating lymph node macrophages to produce plasma cell growth factors. Finally, the
Human Vaccines & Immunotherapeutics
researchers found that TLR5-mediated sensing of the microbiota also impacted antibody responses to inactivated polio vaccine, but not to adjuvanted vaccines or the live-attenuated yellow fever vaccine. The study results reveal an unappreciated role for gut microbiota in promoting immunity to vaccination. Senior study author Dr Bali Pulendran, Professor of Pathology and Laboratory Medicine at Emory University School of Medicine and Yerkes National Primate Research Center, commented: “These results demonstrate an important role for gut bacteria in shaping immunity to vaccination, and raise the possibility that the microbiome could be harnessed to modulate vaccine efficacy. The key question is the extent to which this impacts protective immunity in humans.” Dr Pulendran and his team is planning a study in humans to address this issue.
Volume 10 Issue 11
Downloaded by [206.214.12.105] at 15:21 05 November 2015
Challenges on the Way to Polio Eradication Findings of a recent study in the journal PNAS (http://www.pnas.org/content/111/35/ 12889.abstract) are alarming: a mutated polio virus that was able to a considerable extent to escape the protection provided by the current polio vaccine was found in victims of a polio outbreak in the Congo in 2010. The pathogen could also potentially have infected many people in Germany. In 2010, a large poliomyelitis outbreak involving 445 laboratory-confirmed cases occurred in the Republic of Congo. The 47% fatality rate was unusually high, and notably many of those affected had been vaccinated. Half of the patients remembered having received the recommended 3 dose vaccination, which to date has been considered a highly effective tool to prevent poliovirus infection. A group of researcher from the University of Bonn (Germany) together with colleagues from Gabon isolated the poliovirus type 1 responsible for the outbreak and located its evolutionary origins to Southeast Asia. Fatal cases showed evidence for previous vaccination against polioviruses, and the outbreak virus was refractive to neutralization by monoclonal and vaccine-derived antibodies. This pointed to immune escape contributing to the severity of the outbreak.
“We isolated polioviruses from the deceased and examined the viruses more closely,” explained study lead author Dr Jan Felix Drexler. “The pathogen carries a mutation that changes its from at a decisive point.” As a result, vaccine-induced antibodies cannot block the mutated virus and render it harmless. The researchers examined the success with which the new pathogen evades the immune system. They tested blood samples from 34 German medical students, who had all received polio vaccine in childhood. The antibodies readily recognized wild-type poliovirus, but bareyl recognized the mutated virus from the Congo outbreak. The authors estimate that at least one in 5 of the test subjects could have been infected by the mutated poliovirus. To achieve polio eradication, sustained vaccination regimens in polio-free regions, together with clinical and environmental poliovirus surveillance, will be essential. But some other parts of the world, where polio is still endemic, face more basic problems than antigenetically variant polioviruses. Pakistan has recorded 166 cases of poliomyelitis thus far in 2014, up from 93 cases in 2013. According to health officials, this alarming increase is mainly due to the consistent
trend of parents refusing to get the oral polio vaccine (OPV) administered to their children. 149 of the 166 reported polio cases occurred in children who had not received the polio vaccine. The majority of cases (119) have been registered in the Federally Administered Tribal Areas (Fata), where issues of security, Taliban’s ban of vaccination and inaccessibility for healthworkers remain serious concerns. But in the rest of the country, 31 of 47 reported cases affected children who had not received polio vaccine. Thus, even outside Fata, which has often been blamed for blocking polio vaccination efforts, the anti-polio trend is alarming. Different communication strategies have failed to end the misconceptions about the OPV vaccine and convince parents in Pakistan to vaccinate their children. Such behavior has been hampering global polio eradication efforts. In prinicple, chances are good to achieve polio eradication. Like smallpox, successfully eradicated since 1980, poliovirus can only be transmitted from person to person, meaning that there are no reservoirs in animals from which the disease could spread repeatedly. Moreover, polio vaccines offer extraordinary protection. Further increasing vaccination rates may make a polio-free world possible.
Investigational 9-Valent HPV Vaccine could Prevent Almost 90% of Cervical Cancers Since nine human papillomavirus (HPV) subtypes have been found to cause the majority of cervical precancers, a 9-valent HPV vaccine has been developed by Merck. According to a new study in the journal Cancer Epidemiology, Biomarkers & Prevention (http://cebp. aacrjournals.org/content/23/10/1997) such a vaccine could prevent »90% of invasive cervical cancers worldwide, in addition to the majority of precancerous lesions. Currently licensed vaccines include HPV types 16 and 18 (Cervarix) or quadrivalent 6, 11, 16 and 18 (Gardasil), respectively. HPV 16 and 18 are the predominant causative factors of cervical precancers, referred to as cervical intraepithelial neoplasia (CIN) 1, 2 and 3 depending on the extent of abnormality. HPV 6 and 11 are the main cause of genital warts.
www.landesbioscience.com
In 2011, the International Agency for Research on Cancer (IARC) expanded the carcinogens list to include HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. “We wanted to study how many cervical precancers could potentially be prevented by an investigational 9-valent HPV vaccine that provides protection against the HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58,” said study lead author Dr Elmar A. Joura, Associate Professor of Gynecology at the Medical University of Vienna (Austria). “Approximately 85 percent or more of precancerous lesions of the cervix were attributed to the 9 HPV types covered in the vaccine; therefore, if 9-valent HPV vaccination programs are effectively implemented, the majority of these lesions could be prevented.
Human Vaccines & Immunotherapeutics
Joura and colleagues investigated the prevalence and incidence of 14 HPV types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in CIN and adenocarcinoma in situ (AIS). They used data from 10,656 women ages 15–26 years and 1,858 women ages 24–45 years, who were enrolled in the placebo arms of 3 clinical trials testing quadrivalent HPV vaccine. Among these women, 2,507 were diagnosed with CIN1, CIN2, CIN3, or AIS. The researchers estimated the incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by the investigational 9-valent vaccine.
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After adjusting for the presence of multiple HPV subtypes in a single lesion, it was found that 7 high-risk HPV types included in the 9-valent vaccine were present in »55% of CIN 1, about 78% of CIN 2, about 91% of CIN 3, and nearly 100% of AIS lesions. Of the 15- to 26-year-old women who had precancers, 54% had a single HPV
infection and 32% were infected with more than one HPV type. Of those aged 24– 45 years with precancers, 59% and 19% were infected with one and more than one HPV types, respectively. The authors concluded that »85% or more of CIN3/AIS, >70% of CIN2, and »50% of CIN1 lesions worldwide are attributed to
the 9 HPV types included in Merck‘s new 9valent vaccine which is under review with the US Food and Drug Administration (FDA). Effectively implemented 9-valent HPV vaccination programs could prevent the majority of CIN2 and CIN3 lesions worldwide, in addition to approximately one-half of CIN1.
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FDA Arants Fast Track Designation for Pfizer’s C. diff Vaccine Candidate As recently announced by Pfizer Inc., the US FDA has granted Fast Track designation to the company’s investigational Clostridium difficile vaccine candidate (PF-06425090). The investigational vaccine, currently in Phase 2 clinical development, is designed to prevent C. difficile-associated disease, which can include life-threatening diarrhea and pseudomembranous colitis. The FDA’s Fast Track approach is a process designed to facilitate the development and expedite the review of new drugs and vaccines intended to treat or prevent serious conditions and address an unmet medical need. The Fast Track designation could help Pfizer pick up some ground in the race to bring the first vac-
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cine for C. difficile-associated disease to the market. Sanofi has a C. difficile candidate vaccine in Phase 3 clinical development, and the French biotech company Valneva expects to initiate Phase 2 studies by the end of 2014. C. difficile, is the most frequent cause of healthcare-associated infections. It is a sporeforming, Gram-positive anaerobic bacillus that produces 2 exotoxins: toxin A and toxin B. It is a common cause of antibiotic-associated diarrhea (AAD) and accounts for 15– 25% of all episodes of AAD. C. difficile infection is known to occur mainly in older adults in hospitals or in long-term care facilities, typically after use of antibiotic medications. But recent studies show that increasingly also
Human Vaccines & Immunotherapeutics
younger and healthy individuals without a history of antibiotic use or exposure to healthcare facilities are affected. Infection with C. difficile places a significant burden on healthcare facilities; it substantially increases hospital costs, hospital length of stay, and contributes to mortality. “C. difficile is a growing, difficult-to-treat healthcare-associated infection,” said Dr. Emilio Emini, Senior Vice President of Vaccine Research and Development for Pfizer. “No vaccine is currently available to prevent the infection-associated disease. In the United States alone, there are approximately 250,000 cases of C. difficile-associated disease, resulting in approximately 14,000 deaths each year.”
Volume 10 Issue 11
ISSN: 2164-5515 (Print) 2164-554X (Online) Journal homepage: http://www.tandfonline.com/loi/khvi20
Human Vaccines & Immunotherapeutics: News To cite this article: (2014) Human Vaccines & Immunotherapeutics: News, Human Vaccines & Immunotherapeutics, 10:11, 3103-3106, DOI: 10.4161/21645515.2014.995038 To link to this article: http://dx.doi.org/10.4161/21645515.2014.995038
Published online: 27 Jan 2015.
Submit your article to this journal
Article views: 17
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=khvi20 Download by: [206.214.12.105]
Date: 05 November 2015, At: 15:21
NEWS Human Vaccines & Immunotherapeutics 10:11, 3103--3106; November 2014; © 2014 Taylor & Francis Group, LLC
Human Vaccines & Immunotherapeutics: News
Downloaded by [206.214.12.105] at 15:21 05 November 2015
Ebola Vaccine Candidates are Tested in Humans It has been >6 months since the Ebola outbreak was declared. Countries hit hardest include Liberia, Guinea and Sierra Leone, but individual cases in the United States and Europe have also made the news. There are no available treatments or vaccine, but many pharmaceutical companies as well as the US National Institutes of Health (NIH) are determined to change that soon. The most advanced vaccine candidate, from GlaxoSmithKline (GSK), is being tested in a Phase 1 trial at the NIH campus in Bethesda (MD, USA). This candidate (cAd3-ZEBOV) employs a chimpanzee-derived replicationdefective adenovirus vector containing 2 Ebolavirus gene segments. The vaccine works by entering a cell, delivering DNA, and expressing Ebola protein for eliciting an immune response. cAd3-ZEBOV has elicited no major side effects so far in healthy volunteers. The trial began in September and should be completed by December. The same vaccine is also being tested in a clinical trial in Cambridge (UK), and the NIH plans to extend the studies
to Mali to assure that the vaccine is safe and effective. Phase 2 trials might begin in early 2015, and could include those at high-risk of Ebola, such as healthcare workers in the 3 most affected countries in West Africa. In a recent assessment, the World Health Organization (WHO) said that the expedited evaluation of trial-ready Ebola vaccines is a high priority, citing 2 promising vaccines: GSK`s cAd3-ZEBOV and rVSV-ZEBOV, which was conceived by the Public Health Agency of Canada in Winnipeg and is being developed by the US company NewLink Genetics. Clinical trials for rVSV-ZEBOV should start very soon. Other vaccines in development, yet not so far advanced, include candidates from Inovio Pharmaceuticals and Johnson & Johnson (J&J). Inovio recently announced that it will advance its DNA vaccine into a Phase 1 clinical trial in a collaboration with the international DNA vaccine manufacturer GeneOne Life Science Inc., Inovio’s Ebola vaccine candidate was designed using the company’s SynCon
technology to provide broad protective antibody and T-cell responses against multiple Ebolavirus strains. Preclinical testing showed that 100% of vaccinated guinea pigs and mice were protected from death after being exposed to Ebolavirus. Unlike non-vaccinated animals, vaccinated animals were also protected from weight loss, a measure of morbidity. Researchers found significant increases in neutralizing antibody titers and strong and broad levels of vaccine-induced T-cells, including killer T-cells, suggesting that this candidate could provide both preventive and treatment benefits. Inovio and GeneOne are conducting pre-IND activities and plan to start a clinical trial in the first half of 2015. J&J’s candidate vaccine recently received fast-track designation from the FDA. Clinical trials are expected to start early in 2015. Most of the experimental Ebola vaccines and therapies have not been tested in the clinic, thus it will be exciting to see if any of them will be successful in protecting humans from Ebola.
Novavax’ H7N9 Avian Influenza VLP Vaccine Positive in Phase 1/2 The clinical-stage biopharmaceutical company Novavax Inc., recently announced positive results from a Phase 1/2 clinical trial of its H7N9 avian influenza virus-like particle vaccine candidate (H7N9 VLP) formulated with their proprietary adjuvant Matrix-M. Novavax focuses on the discovery, development and commercialization of recombinant nanoparticle vaccines and adjuvants. In February 2011, the company was awarded a contract by BARDA valued at up to $179 million for the advanced development of recombinant influenza vaccine products and manufacturing capabilities for pandemic preparedness, and the current Phase 1/2 trial was conducted under this contract. The dose-ranging, randomized, observerblinded, placebo-controlled clinical trial
www.landesbioscience.com
included 610 healthy subjects to evaluate the safety and immunogenicity of the H7N9 VLP vaccine formulated with Matrix-M. The study was designed to determine the contribution of Matrix-M to potential antigen dose-sparing regimens. Study subjects received 2 doses of 15 mg of H7N9 VLP alone, or 3.8, 7.5 or 15 mg of H7N9 VLP in combination with either 25 or 50 mg of Matrix-M, or placebo. Serology was taken on Days 0, 21 and 42. The results showed that the H7N9 VLP vaccine candidate, with and without Matrix-M, was well tolerated and demonstrated a safety profile similar to the company’s prior experience with another saponin-based adjuvant. Matrix-M adjuvanted formulations demonstrated a clear immunogenicity benefit relative to unadjuvanted antigen, and a dose-response within the adjuvanted groups. Even the 3.8mg dose of
Human Vaccines & Immunotherapeutics
antigen with either tested dose of adjuvant gave immune responses significantly greater than 15mg dose without adjuvant, demonstrating a clear antigen dose-sparing effect. Geometric mean titers of hemagglutinationinhibiting antibody after 2 vaccine doses were comparable to those reported in prior studies with another saponin adjuvant when similar antigen and adjuvant doses were compared. Finally, strong neuraminidase inhibiting antibody responses were observed in adjuvanted vaccine groups. “This study represents the first clinical trial of Matrix-M with our VLPs. We are pleased with the performance of Matrix-M in this study, which increases our confidence in the value of this adjuvant and its future application in this and other recombinant nanoparticle products,” said Dr Stan Erck, President
3103
and CEO of Novavax. “Based on the data from this trial, we will discuss future clinical studies with our partner, BARDA. "Given the Matrix-M safety profile and dose response
observed in this study, we believe additional such studies are warranted to identify the best combination of antigen and adjuvant to achieve the greatest practical antigen dose
sparing, consistent with a strong immune response, thus potentially making available the maximum number of doses in a pandemic emergency.”
Downloaded by [206.214.12.105] at 15:21 05 November 2015
Half of all Flu Shots in the US are Provided by Pharmacists In the United States, pharmacies have established themselves as major providers of influenza vaccines in recent years. While public health officials and manufacturers welcome this development because it makes it easier for patients to get vaccinated, physicians have reservations about pharmacies delivering vaccines. In 1999, only 22 states allowed pharmacists to administer flu vaccines. A decade later, all 50 permitted the practice, after the outbreak of the H1N1 virus. Receiving the seasonal influenza vaccine in a pharmacy or drugstore is more convenient than going to the doctor’s office. There is no need for making an appointment, there are many possible locations to go to and longer opening hours, even on weekends. Customers can get immunized spontaneously while shopping.
Drugstores offering immunizations clearly lessens inconvenience as a barrier, but some doctors are concerned. They want to stay tuned into the health of their patients and keep track of who has received a vaccine. Moreover, appointments for flu vaccination often are also used to check up on any chronic conditions, such as diabetes, that affect their patients. “That relationship, knowing the patient, that is important,” Dr Robert Wergin, a family physician in Milford (NE, USA) and president-elect of the American Academy of Family Physicians told the Associated Press (AP). He added that many doctor’s offices have worked to become more convenient by offering same-day appointments for flu shots. Retailers on the other hand emphasize that their expansion into vaccinations is not meant
to replace a primary care doctor visit, and they offer to notify a customer`s doctor about a flu vaccination, if wanted by the patient. “It is all about providing our customers with access to affordable health care,” said Danit Marquardt, a Wal-Mart spokeswoman, to AP. Since 2000, the number of flu vaccines distributed in the US has nearly doubled to 134.5 million in the 2013-4 season. According to Dr Carolyn Bridges, Associate Director for adult immunizations for the US Centers for Disease Control and Prevention (CDC), it is unclear how much of this growth can be attributed to retail locations, but various studies have shown that easy access is a big factor for adults getting immunizations. Today, nearly half of all flu vaccines provided to adults are administered in non-medical settings such as drugstores.
Gut Microbiota Influence Immunity to Vaccination A new study found that mice treated with antibiotics to remove most of their intestinal bacteria or raised under sterile conditions have impaired antibody responses to seasonal influenza vaccination. These findings suggest that antibiotic treatment before or during vaccination could impair responses to certain vaccines in humans. Moreover, the results could also help explain why immunity induced by some vaccines varies in different parts of the world. Researcher from the Emory Vaccine Center in Atlanta (GA, USA) previously analyzed immune responses to influenza vaccination in humans, using the systems vaccinology‘ approach. They observed that the expression of the Toll-like-receptor (TLR) 5 gene a few days after vaccination correlated with strong antibody responses weeks later. TLR5 recognizes flagellin, the protein monomer that makes up the filament of bacterial
3104
flagellam found on nearly all motile bacteria. These findings led the researchers to further investigate the phenomenon in mice; results were recently reported in the journal Immunity (http://www.ncbi.nlm.nih. gov/pubm-ed/25220212). The research team vaccinated mice lacking TLR5 with trivalent seasonal influenza vaccine (TIV) and found reduced antibody titers and lower frequencies of plasma cells in these animals, suggesting a role for TLR5 in immunity to TIV. This was due to a failure to sense host microbiota. Antibody responses in germ-free or antibiotictreated mice were impaired, but could be restored by oral reconstitution with a flagellated, but not aflagellated, strain of E. coli. TLR5-mediated sensing of flagellin promoted plasma cell differentiation directly and by stimulating lymph node macrophages to produce plasma cell growth factors. Finally, the
Human Vaccines & Immunotherapeutics
researchers found that TLR5-mediated sensing of the microbiota also impacted antibody responses to inactivated polio vaccine, but not to adjuvanted vaccines or the live-attenuated yellow fever vaccine. The study results reveal an unappreciated role for gut microbiota in promoting immunity to vaccination. Senior study author Dr Bali Pulendran, Professor of Pathology and Laboratory Medicine at Emory University School of Medicine and Yerkes National Primate Research Center, commented: “These results demonstrate an important role for gut bacteria in shaping immunity to vaccination, and raise the possibility that the microbiome could be harnessed to modulate vaccine efficacy. The key question is the extent to which this impacts protective immunity in humans.” Dr Pulendran and his team is planning a study in humans to address this issue.
Volume 10 Issue 11
Downloaded by [206.214.12.105] at 15:21 05 November 2015
Challenges on the Way to Polio Eradication Findings of a recent study in the journal PNAS (http://www.pnas.org/content/111/35/ 12889.abstract) are alarming: a mutated polio virus that was able to a considerable extent to escape the protection provided by the current polio vaccine was found in victims of a polio outbreak in the Congo in 2010. The pathogen could also potentially have infected many people in Germany. In 2010, a large poliomyelitis outbreak involving 445 laboratory-confirmed cases occurred in the Republic of Congo. The 47% fatality rate was unusually high, and notably many of those affected had been vaccinated. Half of the patients remembered having received the recommended 3 dose vaccination, which to date has been considered a highly effective tool to prevent poliovirus infection. A group of researcher from the University of Bonn (Germany) together with colleagues from Gabon isolated the poliovirus type 1 responsible for the outbreak and located its evolutionary origins to Southeast Asia. Fatal cases showed evidence for previous vaccination against polioviruses, and the outbreak virus was refractive to neutralization by monoclonal and vaccine-derived antibodies. This pointed to immune escape contributing to the severity of the outbreak.
“We isolated polioviruses from the deceased and examined the viruses more closely,” explained study lead author Dr Jan Felix Drexler. “The pathogen carries a mutation that changes its from at a decisive point.” As a result, vaccine-induced antibodies cannot block the mutated virus and render it harmless. The researchers examined the success with which the new pathogen evades the immune system. They tested blood samples from 34 German medical students, who had all received polio vaccine in childhood. The antibodies readily recognized wild-type poliovirus, but bareyl recognized the mutated virus from the Congo outbreak. The authors estimate that at least one in 5 of the test subjects could have been infected by the mutated poliovirus. To achieve polio eradication, sustained vaccination regimens in polio-free regions, together with clinical and environmental poliovirus surveillance, will be essential. But some other parts of the world, where polio is still endemic, face more basic problems than antigenetically variant polioviruses. Pakistan has recorded 166 cases of poliomyelitis thus far in 2014, up from 93 cases in 2013. According to health officials, this alarming increase is mainly due to the consistent
trend of parents refusing to get the oral polio vaccine (OPV) administered to their children. 149 of the 166 reported polio cases occurred in children who had not received the polio vaccine. The majority of cases (119) have been registered in the Federally Administered Tribal Areas (Fata), where issues of security, Taliban’s ban of vaccination and inaccessibility for healthworkers remain serious concerns. But in the rest of the country, 31 of 47 reported cases affected children who had not received polio vaccine. Thus, even outside Fata, which has often been blamed for blocking polio vaccination efforts, the anti-polio trend is alarming. Different communication strategies have failed to end the misconceptions about the OPV vaccine and convince parents in Pakistan to vaccinate their children. Such behavior has been hampering global polio eradication efforts. In prinicple, chances are good to achieve polio eradication. Like smallpox, successfully eradicated since 1980, poliovirus can only be transmitted from person to person, meaning that there are no reservoirs in animals from which the disease could spread repeatedly. Moreover, polio vaccines offer extraordinary protection. Further increasing vaccination rates may make a polio-free world possible.
Investigational 9-Valent HPV Vaccine could Prevent Almost 90% of Cervical Cancers Since nine human papillomavirus (HPV) subtypes have been found to cause the majority of cervical precancers, a 9-valent HPV vaccine has been developed by Merck. According to a new study in the journal Cancer Epidemiology, Biomarkers & Prevention (http://cebp. aacrjournals.org/content/23/10/1997) such a vaccine could prevent »90% of invasive cervical cancers worldwide, in addition to the majority of precancerous lesions. Currently licensed vaccines include HPV types 16 and 18 (Cervarix) or quadrivalent 6, 11, 16 and 18 (Gardasil), respectively. HPV 16 and 18 are the predominant causative factors of cervical precancers, referred to as cervical intraepithelial neoplasia (CIN) 1, 2 and 3 depending on the extent of abnormality. HPV 6 and 11 are the main cause of genital warts.
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In 2011, the International Agency for Research on Cancer (IARC) expanded the carcinogens list to include HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. “We wanted to study how many cervical precancers could potentially be prevented by an investigational 9-valent HPV vaccine that provides protection against the HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58,” said study lead author Dr Elmar A. Joura, Associate Professor of Gynecology at the Medical University of Vienna (Austria). “Approximately 85 percent or more of precancerous lesions of the cervix were attributed to the 9 HPV types covered in the vaccine; therefore, if 9-valent HPV vaccination programs are effectively implemented, the majority of these lesions could be prevented.
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Joura and colleagues investigated the prevalence and incidence of 14 HPV types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in CIN and adenocarcinoma in situ (AIS). They used data from 10,656 women ages 15–26 years and 1,858 women ages 24–45 years, who were enrolled in the placebo arms of 3 clinical trials testing quadrivalent HPV vaccine. Among these women, 2,507 were diagnosed with CIN1, CIN2, CIN3, or AIS. The researchers estimated the incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by the investigational 9-valent vaccine.
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After adjusting for the presence of multiple HPV subtypes in a single lesion, it was found that 7 high-risk HPV types included in the 9-valent vaccine were present in »55% of CIN 1, about 78% of CIN 2, about 91% of CIN 3, and nearly 100% of AIS lesions. Of the 15- to 26-year-old women who had precancers, 54% had a single HPV
infection and 32% were infected with more than one HPV type. Of those aged 24– 45 years with precancers, 59% and 19% were infected with one and more than one HPV types, respectively. The authors concluded that »85% or more of CIN3/AIS, >70% of CIN2, and »50% of CIN1 lesions worldwide are attributed to
the 9 HPV types included in Merck‘s new 9valent vaccine which is under review with the US Food and Drug Administration (FDA). Effectively implemented 9-valent HPV vaccination programs could prevent the majority of CIN2 and CIN3 lesions worldwide, in addition to approximately one-half of CIN1.
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FDA Arants Fast Track Designation for Pfizer’s C. diff Vaccine Candidate As recently announced by Pfizer Inc., the US FDA has granted Fast Track designation to the company’s investigational Clostridium difficile vaccine candidate (PF-06425090). The investigational vaccine, currently in Phase 2 clinical development, is designed to prevent C. difficile-associated disease, which can include life-threatening diarrhea and pseudomembranous colitis. The FDA’s Fast Track approach is a process designed to facilitate the development and expedite the review of new drugs and vaccines intended to treat or prevent serious conditions and address an unmet medical need. The Fast Track designation could help Pfizer pick up some ground in the race to bring the first vac-
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cine for C. difficile-associated disease to the market. Sanofi has a C. difficile candidate vaccine in Phase 3 clinical development, and the French biotech company Valneva expects to initiate Phase 2 studies by the end of 2014. C. difficile, is the most frequent cause of healthcare-associated infections. It is a sporeforming, Gram-positive anaerobic bacillus that produces 2 exotoxins: toxin A and toxin B. It is a common cause of antibiotic-associated diarrhea (AAD) and accounts for 15– 25% of all episodes of AAD. C. difficile infection is known to occur mainly in older adults in hospitals or in long-term care facilities, typically after use of antibiotic medications. But recent studies show that increasingly also
Human Vaccines & Immunotherapeutics
younger and healthy individuals without a history of antibiotic use or exposure to healthcare facilities are affected. Infection with C. difficile places a significant burden on healthcare facilities; it substantially increases hospital costs, hospital length of stay, and contributes to mortality. “C. difficile is a growing, difficult-to-treat healthcare-associated infection,” said Dr. Emilio Emini, Senior Vice President of Vaccine Research and Development for Pfizer. “No vaccine is currently available to prevent the infection-associated disease. In the United States alone, there are approximately 250,000 cases of C. difficile-associated disease, resulting in approximately 14,000 deaths each year.”
Volume 10 Issue 11
