Human Vaccines & Immunotherapeutics: News

Abstract

Long-term effectiveness shown for Merck’s chickenpox vaccine

Again—no link between vaccines and autism

Experimental ovarian cancer vaccine successful in phase 1

Sinovac’s HFMD vaccine meets phase 3 study goal

A vaccine for long-suffering cat allergy patients

Vaccines are key to breaking infectious disease-malnutrition cycle

Cancer vaccine failures due to the adjuvant IFA?

Novartis’ typhoid vaccine make good progress

Long-term effectiveness shown for Merck’s chickenpox vaccine

A new long-term research project has added weight of evidence supporting the use of Merck’s varicella vaccine Varivax®. Until two decades ago, the varicella virus was so widespread in kids that 90% of adults were believed to be immune due to having contracted the illness when young. Today, nearly 20 years after approval of Varivax, the itchy illness chickenpox is becoming a rarity.

A new study published in the Journal Pediatrics¹ confirms that the varicella vaccine is highly efective. Researchers at Kaiser Permanente monitored 7585 children who received the vaccine between June and November 1995 at age two. Over the next 14 years, the researchers checked every six months to see whether any of the immunized kids—some of whom got second doses between 2006 and 2009—had developed chickenpox or shingles. Parents also had a toll-free number they could call to report if their children fell ill. The average incidence of chickenpox in this vaccinated cohort was 15.9 per 1000 person-years. This is about 10-fold lower than a typical incidence in the prevaccination era, when the rate would have been 140-160 cases per 1000 person-years. Additionally, vaccinated children who contracted chickenpox only suffered from mild symptoms.

The results also showed the incidence of breakthrough cases that among vaccinated children declined over the course of the study, probably as a result of increased herd immunity, suggesting that the vaccine’s protection did not wane over time. None of the kids developed chickenpox after getting a second dose of the vaccine.

“Clearly, the vaccine is a very effective tool in preventing or limiting the severity of chicken pox in young people,” said pediatric infectious disease consultant Dr Randy Bergen, of Kaiser Permanente’s Walnut Creek Medical Center.

Merck dominates the market for varicella vaccines. Varivax was first approved in the US in 1995, followed by ProQuad—a combined vaccine for measles, mumps, rubella and chickenpox—in 2005. When people get to the age when latent infection with the varicella virus can manifest as shingles, Merck offers the shingles vaccine Zostavax®.

Again—no link between vaccines and autism

A lot of the mistrust and scepticism against vaccines has its roots in reports from the 1990s falsely linking autism to vaccines. Although these reports have repeatedly been proven wrong and research has consistently found no link between vaccines and autism, the association has remained lodged in the minds of many.

A new study published in the journal Pediatrics² provides further evidence that there is no link between the administration of vaccines in childhood and autism. The study included more than 1000 kids, 25% of whom had autism. The authors evaluated the association between autism and the level of immune stimulation received from vaccines administered during the first two years of life. Exposure to total antibody-stimulating proteins and polysaccharides from vaccines was determined by summing the antigen content of each vaccine received, as obtained from immunization registries and medical records. There was no correlation between antibody count and incidence of autism up to the age of two when the first vaccine schedule ends.

In this study, the researchers focused on antibody count to assess the credence of claims that the sheer number of vaccines now given to children is behind alleged autism links. The “too many vaccines“ theory must now contend with contradictory data. In addition to finding no link between antibody count and autism, the changes to vaccines in recent years may further help to dispel fears of parents hesitant to vaccinate their children. In the 1990s the immunization program exposed kids to thousands of antigens. Now, thanks to a number of modern subunit vaccines, the whole infant vaccination schedule has 315. In other words, while the number of vaccines given to children is constantly increasing, the opposite is true for the number of antigens contained in these vaccines. Children are exposed to hundreds of viruses and other antigens from birth onward. In theory, a child could respond to thousands of vaccines at once.

Experimental ovarian cancer vaccine successful in phase 1

A novel immunotherapy for treating ovarian cancer has shown promise in a phase 1 study, and has apparently produced complete remission for one patient with advanced stage disease. Results were presented at the American Association for Cancer Research (AACR) meeting in Washington D.C. in early April.

While ovarian cancer is fairly rare, it is an especially deadly form of cancer because it is usually diagnosed only at an advanced stage. The new treatment is a personalized vaccine, created from the tumor cells and blood of women with late-stage ovarian cancer. The patients‘ dendritic cells (DCs) are pulsed with autologous tumor cell lysate supernatants, then put back into the body where they can then fight the tumor.

“Each patient’s tumor is unique like a fingerprint,” explained study lead author Dr Lana Kandalaft, director of clinical development and operations at the Ovarian Cancer Research Center in the University of Pennsylvania’s Perelman School of Medicine. “We’re trying to rewire the immune system to target the tumor.”

The current Phase 1 study found signs of improvement in 19 out of 31 patients. All 19 developed an anti-tumor response, and eight of them had no measurable disease at the end of the trial and are on maintenance vaccine therapy. One of the eight, whose cancer had recurred several times, has been in remission for 45 months according to the study authors.

The researchers added a further step for the 11 patients who responded to the vaccine treatment but still had residual disease. T cells were removed from patients’ blood, stimulated and expanded in the laboratory, and then reinjected into the patients. Following this treatment seven patients had stable disease and one had a complete response. Both treatments were given in conjunction with bevacizumab, a drug that controls blood vessel growth. Side effects were mild.

Sinovac’s HFMD vaccine meets phase 3 study goal

China-based Sinovac Biotech Ltd recently announced that a late-stage trial of its experimental vaccine for hand, foot and mouth disease (HFMD) has met the main study goal of preventing the infection in infants aged 6 to 35 months.

HFMD is caused by enterovirus 71. The disease usually affects infants and children and is spread through direct contact with the mucus, saliva, or feces of an infected person. About 2 million cases of HFMD are reported in China every year.

The trial tested a two-dose regimen of the vaccine in a placebo-controlled Phase 3 efficacy trial in 10,000 healthy infants in China. The observed rate of protection against clinical disease was ~95%. The difference in the rates of serious adverse events in infants who received the vaccine and those who received a placebo was not statistically significant, according to the company. Sinovac is finalizing the clinical report as a part of its documents to be filed with the State Food and Drug Administration (SFDA) of the People’s Republic of China.

While the vaccine is likely to get approval from Chinese health regulators, Sinovac could face competition from two government-sponsored companies also testing HFMD vaccines in late-stage trials. Results from these two studies, conducted by competitors China National Biotec Group and Kunming Institute of Biological Products, are expected later this year.

“If those programs show efficacy rates of greater than 90%, then Sinovac has got a problem,” Aegis Capital analyst Raghuram Selvaraju told Reuters. “If their efficacy rates are below 70%, Sinovac will be the dominant leader in the market.”

Sinovac’s HFMD is expected to be approved by the end of the first quarter of 2014, and launched by the middle of 2014. The facility to manufacture the vaccine has been completed and is ready for inspection by the SFDA.

A vaccine for long-suffering cat allergy patients

A new immunotherapy developed by the UK company Circassia has the potential to make cat allergies an easily treatable condition.

Worldwide, millions of people itch and sneeze from cat allergies, with asthmatic kids being affected particularly hard. In the US, 17% of the population is allergic to cats, and half of them show clinical symptoms if they get to close.

Current treatments are tedious, time-consuming and often related to considerable side effects. Standard treatment is a series of injections of the allergen itself in order to build up immunity. Patients receive weekly injections for about eight months, followed by jabs at longer intervals. The quality of the drug can vary between batches, because companies make it by combing actual material from cats and processing it into injectable form. Alternatively, patients can also take drugs, such as antihistamines or steroids, for the symptoms.

According to Dr Steve Harris, Circassia’s CEO, current treatments are suboptimal: “Efficacy is relatively modest, and the side effects are significant, because you are delivering the very thing people are allergic to,” he said, referring to the injections. “It is also an arduous process and compliance is poor.”

The new treatment developed by Circassia could reduce the number of doctor visits patients need for treatment, and provide a stronger and less compromised remedy. The company’s vaccine consists of synthetic peptides based on cat allergens and is injected four times over 12 weeks. The clinical effect lasts for at least one year, according to trials to date. Vaccinated patients who were exposed to cat dander for three hours a day over four days barely showed noticeable symptoms. “This suggests that they will be able to be in the same room and interact with cats,” said Dr Steve Harris, Circassia’s CEO.

After successfully passing phase 2 trials, the drug is in phase 3 trials, with approval expected as early as 2015. Cirassia is also developing treatments for other allergies, such as house dust mites and ragweed. Merck has developed a new grass-allergy drug in tablet form, which is under review by the FDA.

Vaccines are key to breaking infectious disease-malnutrition cycle

In a recent opinion article in The Guardian, Dr Seth Berkley, CEO of the GAVI Alliance, has warned that the role immunization has to play in breaking the infectious disease-malnutrition cycle is being overlooked. There is increasing evidence that vaccines prevent chronic effects of malnutrition, yet few programs for eradicating hunger factor in immunization. The health sector, not agriculture, holds the key, the GAVI CEO said.

The link between malnutrition and infectious perpetuates a particularly vicious circle. Poor nutrition can weaken the immune system, leaving individuals more vulnerable to infections, and the resulting diarrheal symptoms prevent the body fom absorbing nourishment. From another angle, infectious diseases may tip a child suffering from marginal nutrition into a state of malnourishment. This cycle is a reality for as many as 250 million chidren under the age of five.

There is general agreement that tackling hunger and its causes is a top priority, but little consensus about how this can be best achieved. Most projects focus on the agricultural sector, but none of these campaigns pick up on the growing body of evidence suggesting the need to complement any fight against malnutrition with a fight against infectious disease. In his article in The Guardian³ Dr Berkley lists several examples, such as malnutrition being a risk factor for pneumonia and diarrhoea, which are known to impair the growth of children. Findings in Brazil⁴ demonstrate a bidirectional relationship between nutritional status and the duration of diarrheal illness. A loss of zinc through diarrhea can leave a child prone to further infection, prolonging the diarrhea and further reducing their nutritional intake. One way to avoid this is to vaccinate against rotavirus, which is the leading cause of diarrhoea-related death in children under five, claiming 450,000 lives every year. Besides preventing deaths, vaccines can help to prevent some of the chronic consequences of malnourishment. An Indian study⁵ showed that children with up-to-date vaccines against tuberculosis, diphtheria, tetanus, pertussis, measles and polio were less likely to show signs of stunting.

The GAVI Alliance aims to improve access to vaccines in developing countries and since 2000 has immunized almost 400 million of the world’s poorest children. However, with the global population projected to exceed nine billion by 2050, feeding everyone poses an unprecedented challenge.

Cancer vaccine failures due to the adjuvant IFA?

In the history of cancer vaccine development, it has repeatedly happened that candidates showing great promise in the lab failed in clinical trials later. A new study published recently in Nature Medicine⁶ offers a possible explanation.

Scientists from the MD Anderson Cancer Center in Houston (TX, USA) investigated why cancer vaccine-induced T cells often do not eradicate tumors. They studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund’s adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials to boost the immune response. While peptide/IFA vaccination primed tumor-specific CD8⁺ T cells, they accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven apoptosis, resulting in hyporesponsiveness to subsequent vaccination. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. The study results show that persisting vaccine depots can induce specific T-cell sequestration, dysfunction and deletion at vaccination sites. Short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.

Thus, while IFA succeeds in increasing T cell activity, it also appears to draw their attention away from the tumor. “The body does not know how to deal with the mineral oil [in IFA], and the body cannot get rid of that big blob of vaccine ... that sits under the skin. The T cells go back and try to kill the oil, but they can’t,” explained Dr Willem Overwijk, senior author of the study. The finding could explain why T cell activity can fail to correlate with efficacy.

Of course, the conclusion reached about IFA in mice might not translate to humans, especially since the study looked at activity around the skin and subcutaneous tissue, areas that differ considerably in mice and humans. To address these doubts, Dr Overwijk plans to run a clinical trial of a saline or water-based cancer vaccine later this year. But while removal of IFA should overcome the potential T cell distraction problem, switching IFA for saline could cause cancer vaccines to fail for a different reason. Without IFA kick-starting the immune system, the immune response could be too weak.

Novartis’ typhoid vaccine make good progress

Novartis has successfully completed phase 2 safety studies for its typhoid vaccine candidate and now considers a wider rollout as it pushes to develop a vaccine to eliminate typhoid fever.

Infections with the bacterium Salmonella typhi, the cause of typhoid fever, are a significant public health problem in developing countries where access to clean water and proper sanitation is limited. Every year, 21 million cases and half a million deaths from typhoid fever are counted worldwide. The disease is particularly common in South and South East Asia. Salmonella paratyphi A causes a clinically similar disease (Paratyphoid fever), and its incidence has increased in Nepal, India, Pakistan, China, Vietnam and Indonesia, and in some communities is as common or more common than typhoid fever. There are vaccines for typhoid fever, but these have limited efficacy and are not suitable for use in children, who carry a high burden of disease. No vaccines exist for paratyphoid fever.

The Novartis Vaccines Institute for Global Health (NVGH) is developing a conjugate vaccine, which combines the Vi antigen with the carrier protein CRM197. Conjugate vaccines based on CRM197 have been developed by Novartis for other bacterial infections (e.g., Haemophilus influenzae type b) and they work well in infants. Now that Vi-CRM197 has successfully completed phase 2 clinical trials, Novartis is looking to the next stage of development.

“We have had quite good success so far in early trials, and we hope to be able to roll that out pretty soon,” said Dr Mark Fishman, president of Novartis Institutes for BioMedical Research. Novartis is testing the vaccine in children under the age of 2, a population excluded from the labeling of current treatments like Sanofi’s Typhim Vi.

NVGH also is developing a conjugate vaccine for S. paratyphi A, and since both typhoid and paratyphoid fevers nearly always occur together, the ultimate goal is a bivalent vaccine able to protect against both S. typhi and S. paratyphi A. This bivalent vaccine project is being funded in part by the Wellcome Trust.