Singapore moves center stage in childhood vaccine manufacturing

Medical Tribune July 2009 SFI

David Brill

Singapore is set to produce GlaxoSmithKline (GSK)’s new pediatric pneumococcal conjugate vaccine, following the opening of a S$600 million manufacturing plant in Tuas.

Commercial production of the vaccine, which protects against diseases such as bacteremic pneumonia, meningitis and acute otitis media, is expected to begin in 2011.

The new plant is GSK’s first primary vaccine manufacturing facility in Asia, and only the second site in the world to manufacture the pneumococcal vaccine, after Belgium.

It is also one of the first centers in Singapore to produce biologic drugs – a considerably more complex process than manufacture of non-biologic agents. Four other biologics production plants are under construction in Singapore, and five more have been announced.

“The burden of childhood pneumococcal diseases is considerable and every year around 1 million children under 5 years of age die from pneumococcal infections,” said Mr. Emmanuel Amory, vice president, global industrial operations, GSK Biologics. “This plant is part of GSK’s commitment to ensure maximum availability of this life-saving vaccine.”

The pneumococcal vaccine protects children against Streptococcus pneumoniae and Nontypeable Hemophilus influenza – two of the major pathogens responsible for pediatric illnesses, particularly in developing countries.

The opening of the plant in June by Prime Minister Lee Hsien Loong marked the 50th anniversary of GSK’s business in Singapore – an investment which now exceeds S$1.5 billion and sees over 1,000 staff employed here. The company already has two other production and supply centers in the city-state.

GSK’s Chief Executive Officer Mr. Andrew Witty also announced the establishment of a S$30 million endowment fund to support graduate students in healthcare policy and green chemistry. Singapore’s Economic Development Board will add a further S$20 million, bringing the total fund to S$50 million.

New jab shows promise for CMV prevention

Medical Tribune May 2009 P12

David Brill

American researchers have scored “a home run” in the quest to prevent congenital cytomegalovirus (CMV) infections – a leading cause of birth defects in newborns.

In a recent phase II trial they found that a new vaccine was 50 percent effective at preventing CMV infection among women, after a minimum of 1 year follow-up.

Just 18 of 234 women who were vaccinated went on to develop CMV infection, compared to 31 of 230 women in the placebo group. [N Engl J Med 2009 Mar 19;360(12):1191-9]

Further trials are now needed to confirm whether immunizing mothers will actually translate to a reduction in congenital infections, said lead researcher Dr. Robert Pass.

With phase III trials also required it is likely to be at least 5 years before the vaccine is licensed, he said. It also remains unclear whether CMV immunity persists or would need boosters.

Successful CMV vaccines have so far proved elusive: none are currently licensed despite more than 30 years of research and a ‘top priority’ listing by the US Institute of Medicine in 2001.

“CMV is a very complex virus which has a long-standing relationship with its host,” said Pass, who is professor of pediatrics at the University of Alabama at Birmingham, US.

“When this trial was initiated most people did not think we would find any efficacy for prevention of maternal infection. So to find that the vaccine was actually able to prevent infection in women was essentially a home run.”

Around 0.7 percent of babies are born with a congenital CMV infection – 11 percent of whom are symptomatic at birth. Fetal damage typically occurs in cases where the infection is acquired during pregnancy: around 0.5 percent of such babies die and up to 20 percent have permanent disabilities. [N Engl J Med 2009 Mar 19;360(12):1250-2]

CMV is endemic in Singapore – the virus was present in 87 percent of antental women screened at KK Women’s and Children’s Hospital (KKH) from 1997 to 1998. [Singapore Med J 2000 Apr;41(4):151-5]

Dr. Lai Fon Min, a consultant and head of the antenatal risk assessment unit at KKH, said that there is an important need for CMV vaccines since there are limitations to both maternal and fetal screening, and no accepted therapy for congenital infections.

“If a highly effective vaccine for CMV is developed there may be justification in introducing it in Singapore as we have a high prevalence rate,” he said, but added that it “remains to be seen” whether routine vaccination would be cost effective.

The vaccine tested by Pass and colleagues comprises 0.02 mg of CMV envelope glycoprotein B, along with 13.25 mg of a squalene-in-water emulsion known as MF59. The rights are owned by Sanofi Pasteur.

The study was not designed to assess outcomes among newborns but the findings appear promising: just one of 81 babies born to vaccinated mothers had CMV, whereas three of 97 babies born to placebo-group mothers were infected.

The trial enrolled CMV-seronegative women who had given birth within the previous year. They were vaccinated at 0, 1 and 6 months, and tested quarterly for CMV infections over 42 months.

Injection-site reactions were more common in the vaccinated women but overall adverse event rates were not significantly different to placebo.

Pass added that vaccination could either be performed in pre-teen girls – potentially in combination with the human papillomavirus vaccine – or in very young children, since they are the main source of CMV infections for pregnant women.

Healthcare systems urged to vaccinate workers

Medical Tribune August 2008 P7
David Brill

Widespread vaccination programs should be introduced for all healthcare workers and backed by the WHO, according to an infectious diseases expert from Mexico City.

Describing healthcare as “a very risky activity,” Dr. Samuel Ponce de Leon told the ICID that death and disease among personnel can have serious consequences for systems that are already short of important resources.

“Healthcare workers are an endangered species and a very reluctant one to be protected. A total of 57 countries, mostly in sub-Saharan Africa but also some Asian countries, face crippling healthcare worker shortages.

“Every health system, hospital, institute and outpatient clinic, private or public, should establish a program to vaccinate all healthcare workers as part of a comprehensive healthcare program,” he said, adding that “the WHO should establish obligatory regulation to protect healthcare workers.”

Hepatitis B, influenza, measles, rubella, tetanus and diphtheria – just some of the diseases faced by healthcare workers – should form the very minimum components of vaccination programs, according to Ponce de Leon.

Workers risk catching a wide range of infectious diseases from their patients if they are not vaccinated, and can be responsible for passing these on to other patients, medics and the community at large.

Compliance to healthcare worker vaccination schemes is typically poor, he said, suggesting that poor communication and lack of knowledge are typically responsible. Workers may also be reluctant to give up their time, have a fear of needles, or perceive vaccination as dangerous or unnecessary.

“Healthcare workers should be clear that compliance to be vaccinated is an ethical duty,” he said.

Despite the obstacles, vaccine uptake can be successfully promoted said Ponce de Leon, citing the example of a hospital campaign in Korea which boosted influenza vaccination rates among workers from 27 to 52 percent. [Infect Control Hosp Epidemiol 2006 Jun;27(6):612-7]

Beyond the basic schedule, vaccination programs could be extended to include hepatitis A, varicella and pneumoccocus, he said.

He added that avian influenza is also an area to consider but several issues remain unresolved as to what the best vaccine is and when best to use it.

New bird flu vaccine promises broad immunity and rapid manufacture

Medical Tribune August 2008 SFXII
David Brill

A new vaccine against the avian influenza H5N1 virus has been shown to be well tolerated and induce high levels of immunogenicity against a variety of strains.

The vaccine is derived from continuous cell culture and could be produced up to 3 months quicker than by using traditional methods, the manufacturers suggest.

Mr. Peter Carrasco, Policy Advisor on Vaccine Security for WHO, said that the vaccine could be useful for protecting against viruses that are currently circulating in infected birds, but added that more research is needed with larger study groups to reconfirm the trial’s findings.

The vaccine was tested in a randomized phase I and II trial involving 275 subjects who received two doses 21 days apart. The results were published in The New England Journal of Medicine.

A dosage of 7.5 mcg without adjuvant induced a neutralizing-antibody response in 76.2 percent of subjects – equivalent to a seroconversion rate of 69 percent. Immunogenicity was seen not only against the clade 1 strain used to produce the vaccine (A/Vietnam/1203/2004), but also extended to the clade 2 and 3 strains.

Conventional H5N1 vaccines are produced using embryonated chicken eggs – a technique that requires the use of an attenuated version of the virus. Cell culture, however, can be used to generate a vaccine from the wild type, thereby eliminating the delay while a modified virus is produced.

“The lag time between receipt of a new virus and delivery of a new vaccine is only something like 12 weeks using our technology, which is about 3 months quicker than can be done with the egg technology,” said Dr. Noel Barrett from the Department of Global Research and Development at Baxter BioScience, who developed the vaccine.

“We’re faster, we’re more flexible, and the process is much more robust in that we’re not dependent on the supply of hen’s eggs, which is an uncertain factor in the event of a pandemic caused by an avian virus.”

Baxter have submitted a licensing application for the vaccine to the European Medicines Agency (EMEA), and expect a decision early next year.

The company has reached agreements with some countries to provide the vaccine in the event of a pandemic and already has the manufacturing capacity to deliver in a relatively short time, Barrett said. The decision whether to implement pre-pandemic vaccination remains a matter of government policy, he added.

One potential drawback to the new vaccine is the need for enhanced biosafety facilities which can handle the virulent wild type virus.

“There are very few facillities which are biosafety level 3, and these are expensive to maintain,” said Associate Professor Paul Ananth Tambyah, head of the Division of Infectious Diseases at the National University Hospital in Singapore, who was also one of the authors of the study.

“Without them it is not safe to manufacture this vaccine,” he said, adding that these manufacturing hurdles would need to be overcome before the vaccine could be used routinely.