Abstract
Early-stage HIV vaccine is broadly immunogenic in clinical trial
HPV vaccine: Two shots may be as good as three
New mosquito-based malaria vaccine
Intradermal influenza vaccine now available in the US
Positive Phase 1 data for NovaDigm’s cross-kingdom vaccine NDV-3
One in ten parents do not follow recommended childhood vaccine schedule
Novel Alzheimer vaccine targets amyloid delivery
Computer model could help plan vaccine supply chain
Early-stage HIV vaccine is broadly immunogenic in clinical trial
A clinical study of an experimental vaccine against human immunodeficiency virus (HIV) evaluated its safety and immunogenicity in a small group of healthy human subjects. The new vaccine candidate consists of a modified vaccinia virus Ankara vector expressing four HIV-1 antigens, namely monomeric gp120 and the fused Gag-Pol-Nef polyprotein from Clade B (MVA-B). The vaccine is designed to train the body’s immune system over time to detect and fight different components of the virus.
A team of Spanish researchers at the National Biotech Centre in Madrid conducted a placebo-controlled clinical trial on 30 HIV-free volunteers to test to what extent a healthy immune system is capable of reacting to the vaccine. MVA-B was found to be safe, well tolerated and elicited strong and durable T-cell and antibody responses. Three-quarters of those who received the MVA-B vaccine developed antibodies against HIV after eleven months. A third of participants developed CD4+ cells while two-thirds developed CD8+ cells—both of which are types of T cells that fend off HIV. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. The study results were recently published in Vaccine1 and the Journal of Virology.2
While 92% of trial subjects developed some immune response to the vaccine, further testing is needed to determine whether that response would protect against infection with HIV. The researchers are planning a study to test whether MVA-B could be used as a therapeutic vaccine.
Study lead researcher Dr. Mariano Esteban says he hopes the vaccine will eventually reduce HIV to “a minor chronic infection.” “If this genetic cocktail successfully passes Phase II and Phase III future clinic trials, and makes it into production, in the future HIV could be compared to herpes virus nowadays,” added Esteban.
Thanks to improved drug therapies people infected with HIV can live longer, but the disease remains incurable and new infection rates remain high in many parts of the world. Furthermore, no HIV vaccine to date has achieved a significant rate of efficacy in preventing disease or infection. The United Nations World Health Organization estimates that more than 33 million people worldwide are infected with HIV.
References
1. García F, et al. Vaccine 2011; 29:8309-16.
2. Gómez CE, et al. J Virol 2011; 85:11468-78.
HPV vaccine: Two shots may be as good as three
ccording to a recent study, two doses of the human papilloma virus (HPV) vaccine may be as effective as the recommended three-dose schedule. The findings are important because vaccine costs and scheduling problems often prevent women from completing the three-dose regimen.
Scientists from the National Cancer Institute (NCI), along with experts from Costa Rica and the Netherlands, followed 7466 women aged 18-25 years in Costa Rica who received three doses of either HPV vaccine (Cervarix) or of a control Hepatitis A vaccine. About 20% of the Cervarix group did not receive all three doses, and thus the researchers were able to follow this incompletely vaccinated group as well. At the end of a four-year follow-up period, women who had received only two doses of Cervarix had protection rates comparable to women who had completed the full three-dose regimen. Additionally, even women who had received only one dose showed some increased protection from the virus, but the number of subjects in that group was relatively small. The findings were recently published in the Journal of the National Cancer Institute.1
“Our study provides evidence that an HPV vaccine program using two doses will work. It may be that vaccinating more women, with fewer doses for each, will reduce cervical cancer incidence more than a standard three-dose program that vaccinates fewer women,” said Dr. Aimee Kreimer, an NCI investigator who led the project.
More research is needed to confirm the study findings. So far researchers have only been able to follow women over the short-term, but the authors say that at least a decade of follow-up is needed to see how long protection may last. Also, the women in the current study were 18–25 years of age, while in the US girls receive the vaccine at 11 or 12 years of age. It is unclear whether younger girls would have a similar response after just two doses. Finally, it is also unclear whether the results would be the same with the other licensed HPV vaccine Gardasil.
Reference
1. Kreimer AR, et al. J Natl Cancer Inst 2011; 103: 1444-1451.
New mosquito-based malaria vaccine
Creating a malaria vaccine within the bodies of mosquitoes is not a new idea, but getting from concept to a safe and effective vaccine has not proven possible to date. A new study published online in the journal Science1 shows that a live attenuated malaria vaccine purified from mosquitoes was safe in human volunteers, but elicited only limited immunogenicity and protection. Animal studies suggest that this limitation could be overcome by intravenous (IV) administration.
“What we believe is needed is a highly effective malaria vaccine. To our minds, that means 80% protective, preferably 90% protective, for at least six months, preferably for several years,” said study researcher Dr. Stephen Hoffman, a medical doctor who founded the company Sanaria Inc. in 2002 with the aim of creating a malaria vaccine.
Malaria is spread via mosquitoes. When an infected insect bites, the malaria parasite called Plasmodium falciparum is passed into human blood. When the parasite reaches the liver, it reproduces and spreads throughout the body to cause malaria.
Mosquito-based vaccines use infected mosquitoes that have been irradiated. These attenuated parasites do still reach the liver, but can no longer reproduce or cause disease. However, their presence still triggers the body’s immune system to elicit a protective immune response. Challenges associated with this concept in the past were that mosquitoes tend to carry diseases besides malaria, and that transmission via mosquitoes is difficult, given the high number of insect bites needed to deliver immunity.
To overcome these problems, researchers at Sanaria raised their own mosquitoes and kept them free from disease except for the malaria parasite. After irradiation, they extracted the insects’ salivary glands to produce the vaccine. The purified irradiated P. falciparum sporozoite (PfSPZ) vaccine was administered to healthy volunteers by needle inoculation in the skin, and was found to be safe. However, only two out of 40 vaccinated people developed immunity to malaria.
Consequently, Sanaria teamed up with researchers from the National Institute of Health (NIH) to experiment with the method of vaccine delivery in animals. Following intravenous (IV) administration of PfSPZ, 71–100 percent of animals developed immunity. Animal experiments demonstrated that IV immunization is critical for inducing a high frequency of PfSPZ-specific CD8+, IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice).
The study results suggest that IV administration of this vaccine could lead to the prevention of infection with P. falciparum malaria. But it remains to be seen whether this will work in people, and there is a need to find an efficient way of administering the vaccine to large populations.
“I don’t think I can stress enough how difficult the concept of mass-producing such a vaccine is, and how the company has done that,” commented Dr. Anna Durbin, Associate Professor for international health at Bloomberg School of Public Health at Johns Hopkins University.
The NIH plans to begin IV human vaccine trials this fall. This route of immunization would be a first for a vaccine and would certainly make mass immunization campaigns difficult.
But even if an IV vaccine cannot be scaled up for mass immunization in countries where malaria is endemic, there could be a smaller market for military recruits, public health workers, students or visitors going to those areas, according to study author and NIH researcher Dr. Robert Seder.
Reference
1. Epstein JE, et al. Science. 2011; In press.
Intradermal influenza vaccine now available in the US
sanofi pasteur’s new intradermal influenza vaccine Fluzone Intradermal offers adults in the US a new immunization option for the 2011-2012 influenza season. The vaccine was licensed by the US Food and Drug Administration (FDA) in May this year and is the first influenza vaccine in the US that uses a microinjection system for intradermal (ID) delivery.
sanofi pasteur has already introduced similar ID influenza vaccines in more than 40 countries including Australia, Canada and countries in Europe. The attractive new immunization option for adults between 18 and 64 years of age may help boost adult flu vaccination rates.
“Adults 18 through 64 years of age have some of the lowest influenza immunization rates in the US despite public health recommendations for everyone 6 months of age and older to receive an annual influenza immunization,” said Dr. Damian Braga, Senior Vice President, Commercial Operations, sanofi pasteur. “Our commitment to introducing new technologies, such as Fluzone Intradermal vaccine, reflects sanofi pasteur’s expertise in developing innovative immunization options that can help foster greater vaccine acceptance among adults.”
Fluzone Intradermal vaccine incorporates a new, easy-to-use, prefilled microinjection system designed to consistently deposit vaccine antigens into the dermal layer of the skin of adults. The dermal layer contains a high concentration of specialized cells known as dendritic cells, which play a key role in generating an immune response. In clinical trials, Fluzone Intradermal vaccine produced an immune response similar to Fluzone vaccine administered intramuscularly (see Human Vaccines News, Policy and Profiles 7-7).
Fluzone Intradermal vaccine features an ultra-fine needle that is only 1.5 mm in length, which is 90 percent shorter than the typical needle used for intramuscular injection of traditional influenza vaccines. The new ID vaccine is also dose-sparing, containing 9 µg of hemagglutinin per strain of influenza in a 0.1 ml dose, compared to 15 µg hemagglutinin per strain in a 0.5 ml dose for other Fluzone vaccines.
Greater convenience and less pain place microneedle systems in a favorable position in the drug-delivery field.
Positive Phase 1 data for NovaDigm’s cross-kingdom vaccine NDV-3
The US company Novadigm Therapeutics recently presented positive Phase I data for its vaccine NDV-3, designed to prevent diseases caused by Candida and Staphylococcus aureus. NDV-3 vaccine was safe, well-tolerated and induced strong antibody and T-cell responses in healthy adults. NDV-3 is the first vaccine known to have demonstrated preclinical protective efficacy against both fungal and bacterial pathogens.
The prophylactic vaccine candidate NDV-3 contains the recombinant Candida surface protein Als3 formulated with the widely used adjuvant Alum. Candidal Als3 is structurally similar to the microbial surface components recognizing adhesive matrix molecule adhesin, clumping factor, from S. aureus. Preclinical studies have shown that NDV-3 confers a high survival rate following a challenge with highly virulent doses of one of several species of Candida or against one of several strains of S. aureus, including methicillin-resistant S. aureus (MRSA). These data provided the foundation for vaccine development against both S. aureus and Candida, which collectively cause 200,000 bloodstream infections resulting in 40-50 thousand deaths annually in the US alone.
The double-blind, placebo controlled Phase I clinical study evaluated the safety, tolerability and immunogenicity of a single dose of the NDV-3 vaccine in 40 healthy adults. Two different doses (30 or 300 µg) were tested, and participants were followed for six months post-vaccination. NDV-3 was safe and well-tolerated at both dose levels. Additionally, both dose levels resulted by day 14 in 100% seroconversion for serum IgG and serum IgA1 with 17- to 59-fold geomean fold rises in IgG and IgA1 titers for both dosages. Geomean titers over the course of 28 days were significantly higher for the 300µg dose than the 30µg dose. The majority of vaccinated subjects demonstrated significant Als3-stimulated production of the cytokines IL-17A and IFN-γ compared to the placebo group.
“The Phase I data show that those receiving NDV-3 demonstrated rapid and robust immune responses, which adds promising initial human safety and immune response data to the extensive preclinical profile for this program”, said Dr. Timothy Cooke, NovaDigm’s Chief Executive Officer. “NDV-3 is an innovative vaccine with significant clinical and commercial potential to protect against diseases caused by these fungal and bacterial pathogens. NovaDigm continues to advance this program into additional clinical and preclinical studies.”
The Phase I data were presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in a poster titled, “First-in-Human Clinical Evaluation of NDV-3: Safety & Immunogenicity of a Vaccine to Prevent Disease Caused by Candida spp. and Staphylococcus aureus” by Dr. John Hennessey, Vice President of R&D for NovaDigm.
One in ten parents do not follow recommended childhood vaccine schedule
According to a recent nationwide US survey, more than one in ten parents use alternative vaccination schedules that differ from the recommended childhood vaccination program for their children. The findings were released in a recent issue of the journal Pediatrics.1
Last year, researchers from the University of Michigan (Ann Arbor) surveyed 771 parents of children between 6 months and 6 years of age. While only 2% refused all vaccines, 13% reported using some type of alternative vaccination schedule, where they delay some shots until their children are older or space shots apart so that their child does not get multiple immunizations at once. And 80-95% of those surveyed who used an alternative vaccine schedule for their children harbored anti-vaccine sentiments.
The study found that children whose parents chose to skip and delay vaccines were also less likely to visit a doctor regularly. “Do parents who follow an alternative schedule have a difficult time finding a physician for their child who supports their vaccination beliefs, or are parents who tend not to engage in regular health care for their children those who also tend to follow an alternative schedule?” the study authors asked, according to the Boston Globe. This question remains unanswered. Measles-mumps-rubella and diphtheria-pertussis-tetanus are the two vaccines skipped most often.
Over the last two decades the number of recommended vaccination shots has risen significantly, from 11 before kindergarten two decades ago to 38 in the same time frame today. Many parents are concerned about the safety of giving young children so many vaccine injections at once. 28 percent of parents who followed the recommended vaccination schedule thought it would be safer to delay immunizations until children are older.
But the US Centers for Disease Control and Prevention (CDCP) insists that the current vaccine schedule is safe for infants and older children. On its website the CDCP acknowledges the increase in the number of immunizations: “It’s not your imagination; there are [a] greater number of shots now than even a few years ago. That’s because as science advances, we are able to protect your child against more diseases than ever before.”
The study authors point out that skipping or delaying even a subset of recommended vaccines could significantly increase the risk of contracting and spreading preventable diseases. For example, a previous study found that children whose parents opted out of one or more vaccines were 22 times more likely than fully vaccinated kids to contract measles and nearly six times as likely to contract pertussis (whooping cough)—though the actual risk of contracting either of these diseases was still very low.
“The results of this study highlight the need to develop interventions quickly to quell the apparently growing concerns among parents about the safety and necessity of recommended childhood vaccines,” concluded study lead author Dr. Amanda Dempsey from the Department of Pediatrics and Communicable Diseases at the University of Michigan.
Reference
1. Dempsey AF, et al. Pediatrics 2011: 128:848-56.
Novel Alzheimer vaccine targets amyloid delivery
A new vaccine candidate against Alzheimer’s disease (AD) targets both amyloid and the protein RAGE (receptor for advanced glycation endproducts), which binds to amyloid and transports it into the brain. Early results have shown improved cognition and memory in animal models of AD.
In AD, the amyloid protein accumulates in the brain, nestling between the neurons and forming impassable plaques, instead of being metabolized naturally. RAGE can bind amyloid and transport it to the brain, and also has been shown to contribute to the inflammation and damage that amyloid causes to the brain’s nerve cells. Amyloid and the way it gets to the brain could be targets for a new AD vaccine. Scott Webster, a graduate student who is studying the disease in the lab of Dr. Alvin Terry, Professor of Pharmacology and Toxicology at Georgia Health Science University (Augusta, GA), was recently awarded the 2011 Darrell W. Brann Scholarship in Neuroscience for this work.
“Unfortunately, all of the vaccines for Alzheimer’s that have been through clinical trials have failed,” said Scott Webster. “Part of the reason why could be that they’re just not comprehensive enough. Most only target amyloid. Our hope is that by taking a more encompassing approach, we will be more effective. So far, that is exactly what we’re seeing in our experiments.”
The researchers at Georgia Health Science University hope that their new vaccine, targeting RAGE and amyloid, will be able to use the body’s own immune system to protect against overproduction and eventual build-up of the same two proteins. Their vaccine can be administered orally without an adjuvant. The researchers hope that by targeting RAGE protein and changing the route of immunization, inflammatory side effects (like swelling of the brain) often seen with other candidate AD vaccines can be minimized.
“That’s a relatively new idea,” Webster said. “By using the immune system that’s endogenous to our gut, we can skew the body’s response away from the inflammatory and toward a more robust antibody response, bypassing some of the side effects.”
Even though the preliminary results in animals are promising, there are many unknowns about the potential vaccine. Better understanding of the basic science and mechanism of action of this novel candidate vaccine and larger animal studies are needed.
Computer model could help plan vaccine supply chain
Proper planning using computational modeling could help introducing new vaccines —like rotavirus and pneumococcal conjugate —into existing immunization programs in developing countries. Storage problems and transportation bottlenecks that can decrease availability of existing vaccines by as much as two-thirds could be prevented, according to a recent study published in the American Journal of Public Health.1
Thousands of West African children die every year from rotavirus and pneumococcal diseases such as pneumonia. The Expanded Program on Immunization (EPI) is a World Health Organization (WHO) initiative that aims to make effective vaccines available to all children around the world. But due to limited storage space and transport capacities in developing countries, vaccines could expire if not properly stored or delivered quickly enough.
Researchers at the University of Pittsburgh, who are part of the Bill and Melinda Gates Foundation funded Vaccines Modelling Initiative, investigated whether introducing the rotavirus and pneumococcal conjugate vaccines would overwhelm existing supply chains (i.e., the series of steps required to get a vaccine from the manufacturers to the target population). They developed a computational model to determine the impact of introducing these new vaccines to Niger’s EPI vaccine supply chain. The study researchers found that introducing either the rotavirus vaccine or the 7-valent pneumococcal conjugate vaccine could overwhelm available storage and transport refrigerator space, creating bottlenecks that would prevent the flow of vaccines down to the clinics. As a result, the availability of all WHO EPI vaccines to patients might decrease from an average of 69% to 28%. Addition of refrigerator and transport capacity could alleviate this bottleneck.
“Our study highlights the importance of prior planning when introducing new vaccines to avoid last-minute temporary fixes,” said study lead author, Dr. Bruce Y. Lee, Assistant Professor of Medicine, Epidemiology and Biomedical Informatics at the University of Pittsburgh. “New vaccines may not fit smoothly into supply chains and therefore fail to reach their target populations easily. These problems may prevent other vaccines from reaching clinics as well. Manufacturers and policymakers should consider vaccine quantity and packaging before designing vaccines and introducing them in unfamiliar areas with limited resources.”
The study’s predictions are similar to what happened in 2006 and 2007 when rotavirus vaccine was introduced in Latin America. Bulky vaccines displaced existing EPI vaccines in already limited refrigerator space, and health care workers had to carry additional thermoses to transport the new vaccines. Large stocks of vaccine expired unused.
Dr. Lee thinks that computational models can help decision-makers plan and understand complex systems. “Although computational models have been widely used in similar logistics planning in many other industries, such as transportation, manufacturing, the military and aerospace, their use in public health has been comparatively limited,” he said. “These models could be a very helpful tool for health workers to plan vaccine supply chains.”
Reference
1. Lee BY, et al. Am J Public Health 2011; In press.