Human Vaccines and Immunotherapeutics: News

Abstract

GSK`s Synflorix: Highly effective at preventing invasive pneumococcal disease

Positive phase 1 interim results for killed whole-virus HIV vaccine

Therapeutic HBV vaccine drives immune responses in liver

New tuberculosis vaccine candidate to enter the clinic

Novartis receives positive CHMP opinion for MenB vaccine Bexsero

New research points way to faster flu vaccines

New Meth vaccine shows promise in animals

RTS,S malaria vaccine reduces malaria by approximately one-third in African infants

Two studies on optimal timing for measles vaccination

Delaying measles vaccination in infants not only increases their risk to develop the disease, but may also be associated with increased adverse events upon immunization. Two recent studies found that there is a relatively precise window of time for the measles, mumps, and rubella (MMR) vaccination, and missing the window comes with its own set of risks.

Medical authorities recommend that the first dose of MMR vaccine should be given at 12—15 mo of age, followed by a second dose at 4—6 y. However, some children receive their first dose much later, if their parents choose to follow alternative immunization schedules. Some doubts revolve around the immediate side effects of the vaccine, which include fevers typically within 7—10 d of immunization. These fevers are also connected with febrile seizures, although both of these adverse events are rare.

A new study published in the journal JAMA Pediatrics¹ examined the effect of age on the risk of fever and seizures following immunization with measles-containing vaccines in children. Researchers from Kaiser Permanente, led by Dr Nicola Klein, looked at more than 840000 children 12—23 mo of age who had received a measles-containing vaccine from 2001 through 2011. They measured fever and seizure events occurring during a 42-d post-immunization observation period.

Generally, fevers and seizures were rare adverse events, occurring in <1% of the 840.000 vaccinations reviewed in this study. However, the researchers found that delaying MMR vaccination only worsened the outcomes. Children who received the first dose at 16—23 mo were twice as likely to develop seizures after vaccination than children who immunized at 12—15 mo. The relative risk of post-immunization fevers was also significantly increased by delayed immunization. The study results highlight the importance of timely immunization of children with the first dose of measles-containing vaccines.

In an accompanying Editorial,² Drs Kristen Feemster and Paul Offit commented: "The results from this study should provide evidence that if vaccine safety is a concern, the currently recommended schedule is the best choice for preventing disease and minimizing adverse events."

Another study in the journal Pediatrics³ looked more closely at the timing of the first measles vaccination, currently recommended at 12—15 mo of age, and its impact on the risk of developing measles. This matched case-control study included only children (5—17 y of age) who had received two doses of measles-containing vaccine: a total of 102 cases and 510 matched controls. The great majority of cases (89%) were in patients 13—17 y old. The Canadian research team found that the risk of measles in 2-dose recipients was 2- to 4-fold higher when measles vaccine was first administered at 12 vs. ≥15 mo of age, with no significant effect of the age at second dose. The mechanism remains unknown, but vaccine failures in a 2-dose recipients could have substantial implications for measles elimination efforts through 2-dose vaccination. The authors concluded that the optimal age at first dose may warrant additional evaluation.

Chinese scientists develop bird flu vaccine

A team of Chinese scientists recently announced that they have developed a vaccine for the H7N9 avian influenza virus, which has killed at least 45 people in China since March. They believe the vaccine could be ready to launch in six months.

The vaccine was jointly developed by the First Affiliated Hospital of Zhejiang University's School of Medicine, the University of Hong Kong, the Chinese Centre for Disease Control and Prevention, the National Institute for Food and Drug Control, and the Chinese Academy of Medical Sciences, and it is the first such influenza vaccine developed by Chinese scientists. The project was sponsored by the Ministry of Education and experts from infectious diseases institutes around the country were recruited.

According to Dr Hangping Yao, a spokesman for the team, which is part of a state-run laboratory at the hospital affiliated with Zhejiang University's School of Medicine, researchers had spent six months isolating virus strains for the vaccine. Most of the H7N9 cases seen on mainland China occurred in Zhejiang province, providing researchers there with ample samples to study.

"Unlike other virus laboratories that need further help from the CDC and World Health Organisation to confirm and identify virus strains, we have our own medical center, hospital, clinics and all related experts to provide comprehensive backup," said Dr Yao. "Before the vaccine can be put on the production line, manufacturers need to spend at least half a year going through several processes, including pilot tests, human trials, and drug approvals".

Two manufacturers are interested in producing the vaccine: the Hangzhou-based Zhejiang Tianyuan Bio-Pharmaceutical and the Beijing Biological Products Institute. H7N9 vaccines are being developed in other countries, including the US, Canada, and Taiwan.

Influenza vaccination reduces risk of heart attack and stroke

A correlation between influenza vaccination and decreased risk of heart attack was previously reported, and a new more definitive analysis confirms this trend. In a meta-analysis of six randomized clinical trials, influenza vaccination was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease.

The study, recently published in the Journal of the American Medical Association (JAMA),⁴ aimed to determine whether influenza vaccination is associated with the prevention of cardiovascular events. An international team of researchers looked at six randomized clinical trials (6735 subjects) comparing influenza vaccine vs. placebo or control in those at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events. The authors found a particularly pronounced association among patients that were considered high-risk because of their active coronary disease. Patients who had recently had a heart attack showed a 55% reduced risk of a further major cardiac event if they were vaccinated against influenza. Looking at a broader patient population, influenza vaccination was linked to a 36% reduction in the risk of having a heart attack, stroke or other major cardiac event.

The data of this meta-analysis clearly indicate that influenza vaccination has an effect on cardiac disease; however, a causal relationship remains to be established. A large, well-powered, multi-center trial is needed to address these findings and to assess individual cardiovascular end points.

In an accompanying JAMA editorial,⁵ Dr Kathleen Neuzil from PATH dissects the meta-analysis before calling for healthcare professionals to push for 100% vaccination of their communities.

Two-dose vaccination program shows positive impact on varicella incidence

According to a recent study in the journal Pediatrics,⁶ the introduction of the 2-dose varicella vaccination program led to a substantial decline in varicella incidence, hospitalizations, and outbreaks. The high levels of immunity in the population also conferred protection on infants, who are not eligible for varicella vaccination, and on adults, in whom vaccination levels are low.

Primary infection with the varicella zoster virus causes chickenpox, a highly contagious disease that usually presents with an itchy skin rash and oral cavity sores, sometimes accompanied by nausea, loss of appetite, aching muscles, and headache. Chickenpox has low mortality, although it is generally more severe in adult men than in women or children. Non-immune pregnant women and those with a suppressed immune system are at highest risk of serious complications.

After introduction of one-dose varicella vaccination for children in the US in 1995, a second dose was recommended in 2006 to further decrease varicella disease and outbreaks. A team of researchers from the Centers of Disease Control and Prevention (GA), Philadelphia Department of Public Health (PA) and County of Los Angeles Department of Public Health (CA) looked at the impact of this routine two-dose varicella vaccination program on varicella incidence, severity, and outbreaks in two active-surveillance areas for varicella. Incidence rates and disease characteristics in Antelope Valley (AV) in California and West Philadelphia as well as varicella outbreak characteristics in AV during 1995—2010 were examined.

The results showed that in 2010 varicella incidence was 0.3 cases per 1000 population in AV and 0.1 cases per 1000 population in West Philadelphia. These are 76% and 67% declines, respectively, since 2006, and 98% declines in both sites since 1995. Incidence declined in all age groups during 2006—10. Looking at disease severity during 2006—2010, most vaccinated case patients has fewer than 50 lesions with no statistically significant differences among subjects who had received one or two doses (63% vs. 70%). Varicella-related hospitalizations during 2006—2010 declined >40% compared with 2002—2005, and >85% compared with 1995—8. The number of outbreaks in AV was also greatly reduced from 236 during 1995—1998 to 47 during 2003—2006 and only 12 during 2007—2010. The authors concluded that varicella incidence, hospitalization and outbreaks declined substantially during the first five years of the two-dose vaccination program.

WHO prequalifies Chinese-produced Japanese encephalitis vaccine

The World Health Organization (WHO) has recently added a vaccine against Japanese encephalitis (JE) to its list of prequalified medicines. Developed and produced by the China National Biotec group (CNBG), this new JE vaccine is the first Chinese-produced vaccine to be prequalified by WHO.

JE is a mosquito-borne flavivirus infection that causes severe disease involving inflammation of the brain. It is major public health problem and is endemic with seasonal distribution in parts of China, south-east Russian, and south and south-east Asia. Since there is no specific treatment for JE, supportive care in a medical facility is important to reduce the risk of death or disability. The disease is preventable by proven effective vaccines.

The new JE vaccine, manufactured in China, needs to be given in only one dose, can be used for infants, and is less expensive than other JE vaccines. It sells for $0.30 per dose, compared with the JE vaccine recently introduced by the Indian manufacturer Bharat Biotech that costs $2.60 per dose on the open market. The Chinese vaccine received WHO prequalification after closely collaborating with PATH, and the Bill and Melinda Gates Foundation also provided support through a $39 million grant to PATH.

"We were able to support the clinical trials, to help CNBG install a facility up to international standard, and to help them improve their systems and processes," PATH's Vaccine Access and Delivery Program director Dr Kathleen Neuzil told Financial Times' blog beyondbrics.

When WHO adds a vaccine to its prequalified list, it means that the organization has given the vaccine its stamp of approval for safety and efficacy, and United Nations procuring agencies can source the vaccine. The Chinese vaccine is available thanks to several years of collaboration between WHO and authorities in China on vaccine production standards and regulation.

"This is a welcome development both in the fight to protect children in developing countries from JE and in the future availability of vaccines more generally, as China is now producing vaccines up to WHO standards," said WHO Director-General Dr Margaret Chan. "There is a huge potential for vaccine manufacture in China and we hope to see more and more Chinese vaccines become WHO prequalified. The whole world will benefit."

The GAVI Alliance will consider opening a window for financial support for JE vaccine. If approved, eligible countries would be able to apply for GAVI support from 2014, with UNICEF leading the international procurement efforts for the vaccine.

Phase 3: RTS,S almost halves malaria cases in young children

GlaxoSmithKline (GSK) recently presented results from a large-scale Phase 3 trial, showing that their malaria vaccine candidate RTS,S continued to protect young children and infants from malaria up to 18 mo after vaccination. Based on these data, the company plans to submit a regulatory application to the European Medicines Agency (EMA) in 2014. Should RTS,S receive a positive scientific opinion by EMA, the vaccine could become available as soon as 2015.

The Phase 3 trial included >15 000 children in seven countries, making it Africa's largest-ever clinical trial. Th efficacy and public health impact of RTS,S were evaluated in the context of existing malaria control measures, such as insecticide treated bed nets which were used by 78% of children and 86% of infants in the trial. Study subjects were followed for 18 mo post vaccination. The vaccine showed an acceptable safety and tolerability profile during the 18-mo follow-up. Children aged 5—17 mo at first vaccination experienced 46% fewer cases of clinical malaria compared with a control vaccine group. Severe malaria cases and malaria hospitalizations in this group were reduced by 37% and 42%, respectively. Infants aged 6—12 wk at first vaccination had 27% fewer cases of clinical malaria in the 18-mo study period. Reduction of severe malaria cases and malaria hospitalizations by 15% and 17%, respectively, were not statistically significant. Overall, vaccine efficacy was found to declined over time: previous results from one-year follow-up of the Phase 3 trial showed that efficacy was 56% against clinical malaria for the 5—17 mo-old age group and 31% in the 6—12 wk-old age group.

As seen in earlier clinical trials, RTS,S provides only incomplete immunity. However, with malaria killing 660 000 people annually, the potential of even an imperfect vaccine is huge.

Sir Andrew Witty, CEO of GSK, said: "We are very encouraged by these latest results, which show that RTS,S continued to provide meaningful protection over 18 months to babies and young children across different regions of Africa. While we have seen some decline in vaccine efficacy over time, the sheer number of children affected by malaria means that the number of cases of the disease the vaccine can help prevent is impressive. These data support our decision to submit a regulatory application for the vaccine candidate which, if successful, would bring us a step closer to having an additional tool to fight this deadly disease. We are grateful to the scientists across Africa and GSK and to our partners who have worked tirelessly for almost 30 years to bring us to this point."

RTS,S is the most clinically advanced malaria candidate vaccine. GSK has developed it with the PATH Malaria Vaccine Initiative (MVI), with funding from the Bill and Melinda Gates Foundation to MVI. Further data from 32 mo follow-up and the impact of a fourth dose given 18 mo after the initial three doses are expected to become available in 2014.

Herd immunity protects babies against whooping cough

According to a recent study, adolescent pertussis vaccination appears to be partially effective in preventing pertussis hospitalization among infants. This herd immunity effect likely helps to protect babies before they are old enough to receive their first whooping cough vaccine at two months of age and build immunity against the bacterium.

Whooping cough, caused by the bacterial pathogen Bordetella pertussis, is a highly contagious disease, characterized by severe coughing fits, which produce a high-pitched "whoop" sound in infected babies and children when they inhale air after coughing.

Infants receive their first vaccine at two months of age, followed by another four shots over the next seven years. This allows a gradual building of immunity, but also creates a window in which infants are vulnerable to disease. Previous studies have found that older siblings are often the source of infection for infants who contract the disease. In 2006, tetanus-diphtheria-acellular pertussis (Tdap) vaccination was recommended for universal administration to adolescents, a known source of pertussis in infants, and by 2011, 78% of adolescents in the US had received Tdap.

A recent study published in the journal Pediatrics⁷ examined whether patterns of pertussis hospitalization for infants changed with adoption of Tdap vaccination among adolescents. Researchers from the University of Cincinnati (OH), Vanderbilt University (TN), and the University of Michigan (MI) identified infants younger than 12 mo who had been diagnosed with pertussis. They looked at the years 2000—5 to estimate pertussis hospitalization patterns if Tdap had not been available and compared expected hopsitalization rates with observed rates for 2008—11. The results showed that in 2008, 2009 and 2011 the observed rate of pertussis hospitalization of infants aged one year and under was significantly lower than expected. The disparity was most pronounced in 2011, when without Tdap, there would have been 10.7 hospital visits per 10 000 infants. In reality there were only 3.3.

The data suggest that vaccination of adolescents is reducing the number who may pass the bacterial infection on to their younger unprotected siblings. According to pediatrician Dr Jennifer Shu from the Children's Medical Group in Atlanta (GA), the vaccine helps adolescents and indirectly protects babies even more, making it a win-win situation and with no major downsides. And Dr William Schaffner from Vanderbilt University told CNN: "Now that we have data that it works, we have created another reinforcing reason to bring teens in for vaccination, not only against whooping cough but for other diseases as well."

New developments in nanoparticle-based vaccination

In the recent past, nanoscale-size materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens. Nanoparticles can stabilize vaccine antigens and act as adjuvants, and some are able to enter antigen-presenting cells (APCs) by different pathways, thereby modulating the immune response to the antigen. Two recent studies using nanoparticles as adjuvant and delivery system are highlighted below.

One new study in the journal Nanomedicine⁸ presents a novel vaccine development platform that enables the site-specific conjugation of synthetic lipid adjuvants to recombinant protein. An Australian research team used a polytope "string-of-beads' approach to produce a synthetic gene incorporating seven Streptococcus pyogenes M protein strain-specific antigens and a conserved M protein antigen. After expression, the synthetic protein was attached to a lipoamino-acid-based adjuvant, and nanoparticles (40nm diameter) of an optimal size for stimulating antibody-mediated immunity were formed upon the addition of these lipoproteins to aqueous buffer. Mice vaccinated with the candidate vaccine produced antigen-specific IgG antibodies against all eight antigens contained in the vaccine, without the need to formulate with additional adjuvant. These antibodies bound M proteins from Group A Streptococcus strains represented within the recombinant antigen sequence. This technology facilitates the simple and efficient production of homogeneous, chemically-defined, semisynthetic lipoprotein vaccines.

Another recent study in the journal Science Translational Medicine⁹ describes a pulmonary vaccination strategy combining Toll-like receptor (TLR) agonists with antigen-carrying lipid nanocapsules [interbilayer-crosslinked multilamellar vesicles (ICMVs)], which elicit high-frequency long-lived antigen-specific effector memory T-cell responses at multiple mucosal sites. Researchers from the Massachusetts Institute of Technology (MIT) tested protein- or peptide-loaded ICMVs combined with two TLR agonists (polyI:C and MPLA) in mice using the pulmonary route of immunization. The candidate vaccine was found to be safe and well tolerated, and led to increased antigen transport to draining lymph nodes compared with equivalent subcutaneous vaccination. This response was mediated by the vast number of APCs in the lungs. The researchers found that nanocapsules primed 13-fold more T cells than did equivalent soluble vaccines, elicited increased expression of mucosal homing integrin α₄β₇⁺, and generated long-lived T cells in both the lungs and distal mucosa strongly biased toward an effector memory (T_EM) phenotype. These T_EM responses were highly protective in both therapeutic tumor and prophylactic viral vaccine settings. The presented data suggest that targeting cross-presentation—promoting particulate vaccines to the APC-rich pulmonary mucosa can promote robust T-cell responses for protection of mucosal surfaces.

The ICM- lipid nanocapsules method has been licensed to the US startup company Vedantra for bringing such a product candidate to a clinical trial.