Giving It Our Best Shot

By Yas Mamemachi

Osaka, Japan

Dr Tanaka who possesses the spirit of Osaka (Photo by Yas Mamemachi)

Have some korokke? I bought them on the corner. These go well with beer,” Tanaka says with a smile after showing up in a hotel room in downtown Osaka.

Korokke are deep fried mashed potatoes covered in bread crumbs. The word is the phonetic equivalent of the French term “croquette.”

Most Japanese probably have no clue what the original French food is like, but korokke is a firmly established “Western” food for many Japanese.

And, they are good. Eating korokke with beer makes the conversation go smoothly.

“We were too successful,” Tanaka starts through a mouthful of korokke.

According to his paper, until the late 1940s the classical childhood vaccine-preventable diseases, or VPDs such as diphtheria, pertussis, tetanus, polio, measles, smallpox, and tuberculosis, were endemic in Japan, as was Japanese encephalitis, or JE.

They were the major causes of death among children younger than five--more than 400,000 reported cases-- and responsible for more than 30,000 reported deaths each year in the late 1940s.

However, while vaccination-related laws were maintained and national immunization programs introduced, the situation has dramatically changed.

The paper says, “Smallpox had been eradicated in Japan as of 1955, and the incidence of diphtheria, pertussis, polio, and JE was reduced by more than 90% by the end of the 1960’s, when compared with the pre-vaccine era.”

“Everything had been accomplished too successfully, so that we misunderstood that we did not have to worry about such vaccine-preventable diseases anymore,” says Tanaka.

But outside Japan a different way of thinking held away, which is that vaccination practices had to be maintained, otherwise vaccine-preventable diseases would return, though they might seem to be eradicated.

“And the issues of vaccine adverse events, or VAEs, came to the surface. The Ministry of Health, Labor and Welfare lost lawsuits over VAEs in the 1970s and 80s,” says Tanaka. “The consequences are devastating.”

They tightened the Japanese immunization program and frozen further development of new vaccines for about two decades.

“Let’s take Hib or Hemophilus influenzae type B vaccine as an example,” Tanaka continues.

Once they are infected by Hib, some children may develop meningitis, possibly causing residual disabilities in their brains. It has been known that meningitis is transmittable so it is critical to maintain higher immunization coverage against the disease for children in society.

In other words, the disease is barely transmitted among children as long as the higher immunization coverage for children in society is maintained, and almost all are already immunized.

The United States exemplifies this ideal situation. In the United States, almost no child has suffered from Hib in recent years, since about 90% of all children from the age of two are vaccinated against Hib.

In Japan, several hundred children are infected by Hib every year, and many of them suffer from meningitis-related residual disabilities in their brains, since children at a certain age are not mandatorily vaccinated against Hib.

“What if some children remain disabled and are bedridden for life? We will have to bear a huge social cost, not to mention that those children’s lives will be devastated.”

However, the Hib vaccine was not licensed in Japan until 2007. Immunization programs have been constantly improved in many countries, and the process accelerated in the 1990s after new antigens, including Hib, as well as combination vaccines of critical antigens were developed and licensed in developed countries other than Japan.

In Japan, only two vaccines, the inactive hepatitis A vaccine and the measles-rubella combination vaccine (MR vaccine), were licensed from 1989 to 2006, chiefly due to the greater damage incurred by the Japanese Ministry of Health, Labor and Welfare after they lost lawsuits over VAEs from the 1970s to the 1990s.

In contrast to programs in the UK, the US, and other countries, the Japanese national immunization program is heavily based on law. Introduction of new antigens to the program requires discussion and approval by the national parliament.

Revision of technical and programmatic details also requires the scrutiny of legal officials in the cabinet or the Ministry of Health, Labor and Welfare, a process in which legal and administrative priorities may take precedence over scientific evidence.

According to Tanaka’s paper, from 1976 to 1992, the Japanese Supreme Court and the Tokyo High Court ruled that adverse health events seen in plaintiffs were causally related to immunizations they had received under the national immunization programs and that these vaccine adverse events were caused by the Ministry of Health, Labor and Welfare’s negligence in ensuring safety.

“No vaccination programs are conducted without any risk of vaccine adverse effects,” says Tanaka. “In other words, vaccine adverse effects are nobody’s fault. However, the Ministry of Health, Labor and Welfare, which had been promoting the Japanese immunization programs, were criticized by media, and the medical experts who were working for the programs and were supposed to back up the ministry kept their mouths closed. Consequently, the ministry decided to promote the programs in a less passionate manner.”

The difficulty of vaccine adverse effects is that there are all types of vaccinations except polio in which no causal relationship between a vaccination and its vaccine adverse effects has been medically proved.

According to Tanaka, the only way to figure out a causal relationship between a vaccination and its vaccine adverse effects is to compare one group of vaccinated children and another of non-vaccinated children. Other than that, it can be theoretically explained, but that method is not evidential.

In the case of vaccinations with a high possibility of vaccine adverse effects, which are not likely to be introduced as part of a national immunization program, such comparative studies are easier to work with due to the low parameters.

However, it is impossible to investigate any vaccine adverse effect, which might occur in about one out of one million children. The fact is, in case of immunizations with such a low possibility of vaccine adverse effects, the above-mentioned comparative study is difficult to carry out, since about one million babies are born every year in Japan.

“Moreover, there is a diehard myth that many Japanese, including some medical practitioners, still believe, which is that sickness must be caused by some kind of vaccine adverse effects if any child becomes sufficiently ill one to two weeks after they were immunized,” says Tanaka.

“For instance, about 90% of children under the age of two receive vaccinations in Japan. That means about 900,000 children under the age of two get vaccinated. So, you would be wondering if some of the children at that age might get sick due to a variety of reasons in the period of one to two weeks after they were vaccinated.”

However, some people try not to bring such a logical perspective when thinking about their own children who may become ill after being vaccinated, Tanaka continues. “The problem is we cannot deny their argument: Vaccine adverse effects might cause such illnesses, which is highly unlikely, since it is almost impossible to prepare a sufficient amount of data to completely deny such a possibility.”

Your call

One of few good things to come out of these events is that all the stake holders, not only physicians but also guardians/parents, have been reminded of the basic but most important fact that guardians must decide whether or not their children should be vaccinated.

“We haven’t touched that matter for years,” Tanaka says. “Immunization had been a kind of social obligation until the national immunization law was revised in the 1990s. After the revision, legally speaking, guardians have to be fully informed about any immunization given to their children before they receive it. However, general practitioners, who mostly conduct immunizations, rarely carry out such informed immunization practices.”

According to Tanaka’s paper, the current national immunization programs mandate that the administration of such programs is the responsibility of each municipality.

There are approximately 1,800 municipalities in Japan. Nearly all of them lack technical officers with sufficient knowledge of immunization to monitor the quality of such programs.

As a result, almost all the municipalities depend on the Ministry of Health, Labor and Welfare for technical advice on program implementation.

However, the ministry and related institutions have no national immunization program office to collect epidemiological and programmatic information on immunization and coordinate medical professionals in advising municipality governments.

At the community level, immunization is almost always contracted to medical associations in each municipality, most of whose members are general practitioners.

In reality, few general practitioners have current knowledge of immunization practice and epidemiology. A few of them have a strong background in pediatrics and infectious diseases, though.

“Informed immunization takes more time than simply giving an injection. So, obviously, many local general practitioners who are not interested in immunization and vaccine adverse events are not actively engaged in informed consent for immunization. I would not be surprised to learn that a professional who is contracted out for the job could provide his or her best service for customers,” says Tanaka.

The root of the problem is that VAEs are not recognized as a major issue by Japanese pediatricians. Tanaka says he remembers at least one VAEs-related story being published in every issue of an academic journal for pediatricians in the US when he worked for the CDC.

In other words, topics on the causal relationships of VAEs are frequently discussed and revised and shared by many American pediatricians. What makes such discussion and research work possible is the accumulation of hard evidence on causal relationships.

These data are publicly available, so most Japanese experts can access them. However, Tanaka wonders if many actually read such journal articles and check the data. He says that he has recently recognized a few Japanese reviews on the related English-language literature that was internationally released.

“In short, few Japanese medical researchers specializing in immunization are interested in VAEs because they have been allowed to say that VAEs are chiefly the government’s issue, not theirs.”

Those who are negative about the issue of VAEs are not only at the bottom of the pyramid of the national immunization system but also at the top.

In the US, the Advisory Committee on Immunization Practice (ACIP), which is the stakeholders meeting for the national immunization program, plays an important role at the top of the program. All the stakeholders from across the nation come to the quarterly meeting and discuss a variety of issues related to immunizations. The policy recommendations based on the discussion are also updated quarterly.

The issues in discussion include the present situation of vaccine preventable diseases in the US—the number of cases, causes of such diseases, types of diseases—and VAEs—symptoms diagnosed.

The ACIP is basically open to anyone and a digest of conference notes is uploaded onto the CDC’s website right after the meeting.

In other words, “Things like who said what about which issues or who voted for or against which issues are disclosed through the website. So any experts might be publicly criticized if they voted for a new vaccine once, but later they say they voted against it, since issues of VAEs come out,” says Tanaka. “The most important thing is that the negative side of the immunization program, which is about VAEs, is seriously discussed, not to mention that further promotion of the program is carried out.”

According to Tanaka, many Japanese experts are of the opinion that a Japanese ACIP should be established only for further promotion of immunization. “That’s way different from the American situation.”

Made-in-Japan quality assured

As our conversation continues, Dr. Tanaka and I have already eaten up the korokke.

“Let’s get out of here and go down to Shinsekai (the “new world” in English), the name of the place around the Tsutenkaku tower, and eat kushikatsu, one of the local favorites,” says Tanaka, who has already grabbed his windbreaker and is ready to leave the room.

The Tsutenkaku Tower (Photo by Yas Mamemachi)

According to the official website of the Tsutenkaku tower, it was built in 1912. The original tower had a pretty eccentric design that combined the Arch of Triumph and the Eiffel Tower.

Tsutenkaku means “tower reaching heaven,” roughly translated into English. The fact is that the tower was the highest in the East at the time it was built, so it lived up to its name. Unfortunately, it was dismantled in 1943 to supply iron for the Pacific War.

The present tower was reconstructed in 1956 chiefly based on donations from local citizens. That’s why the tower is still called the symbol of Osaka.

Kushikatsu, a so-called gourmet dish for regular people in Osaka, consists of pieces of meat or vegetables sprinkled with bread crumbs, skewered, and deep fried.

There is a legend that says a type of Western dish of meat sprinkled with bread crumbs and deep fried was introduced to Japan in the Taisho era, which was from 1912 to 1926.

Back then, most Japanese did not know how to eat food with a knife and fork. One day a local chef wondered if the meat could be cut into small pieces and then be skewered, which would make it easy for any Japanese person to eat. That was the moment Kushikatsu was born in Osaka.

We enter a Kushikatsu restaurant and sit at a small table. There is a small open container full of Worcestershire sauce. I notice a small note posted on the side of the container, saying please do not dip twice.

“That is the rule when eating Kushikatsu in Osaka,” says Tanaka with smile.

I did not exactly know what the note meant. But I did minutes later when a selection of Kushikatsu was served.

Like most people, I eat Kushikatsu after dipping it into the container of Worcestershire sauce. But I realized I dipped the same skewer again in the middle of eating it.

“You did it, didn’t you? You broke the rule here,” says Tanaka with a big laugh.

Traditional Japanese cuisine is served with many small serving dishes. But here one container of sauce is used by different people throughout the day. Minimum sanitation is maintained by following this simple rule.

That may sound typical for a working class milieu and an unsanitary practice to many, especially people in the West. But at the same time it seems to me that the custom represents a tradition of trust among the people of Osaka, which is a precious commodity nowadays.

As the sound of his laugh faded away, Tanaka started talking about the vaccinations again, saying that, in spite of such chaotic national immunization management, Japan should be proud of having developed some of the best quality and progressive vaccines in the world.

For instance, Japan is one of the first countries to develop vaccines in which no gelatin is used as a stabilization agent.

For years gelatin was used as a stabilization agent for vaccines. For instance, it is contained in measles-mumps-rubella vaccines or MMR, which is one of the most highly effective combination vaccines in the world, even though gelatin is well known as one of the most common allergens.

Tanaka recollected working in the United States, and said that some children developed seizures when they ate jelly beans containing gelatin, an allergen that caused the children’s larynxes to become swollen and made it hard for them to breathe.

“Since similar things could have happened when children were vaccinated, I remembered I was told by some CDC staffers that the Japanese vaccines were safer, probably around 2004.”

The development of a component vaccine against pertussis is another example. Many Japanese might be surprised to learn that a significant number of people, including adults, are still infected by pertussis bacteria, which contain some toxins that cause the disease inside the bacteria.

“If you cough badly for more than a month, you should suspect that you might be infected by pertussis, even if you are adult,” says Tanaka, while recollecting his memories in a university dorm in the UK some years back. “In those days, pertussis was epidemic in my dorm. I could hardly stop coughing and was awakened by such coughing. I think it was a typical symptom of the disease. For some reasons, I did not realize it at the time.”

To immunize for the bacteria, inactivated pertussis vaccine was used for years. In other words, the pertussis bacteria is made inactive by means of chemical agents, and then the inactive bacteria as a whole is injected; it is effective, but it may cause a high fever in many people.

In the late 1970s or early 1980s a new type of vaccine against pertussis, the so-called component vaccine, was developed in Japan. With the component vaccine a component of toxin inside the pertussis bacteria is extracted.

“So the pertussis bacteria as a whole can be injected for immunization, with far less concern for vaccine adverse events such as development of high fever. After its development, the component vaccine method was applied for other vaccinations and turned into the global standard for vaccinations today,” says Tanaka.

“Many Japanese, including myself, should have known these facts before,” I said to him. “I’m sure they should,” he replied.

“What a waste,” I murmured.

“What a waste,” he murmured as well.

The original vaccine against chicken pox is another that Japan should be proud of developing, Tanaka continues. The Research Institute for Microbial Diseases of Osaka University made it a reality.

Although chicken pox is not life-threatening for many people, herpes zoster could cause discomfort to those infected for the rest of their lives.

Hashizume, named after the doctor who invented the vaccine against small pox, is also globally known as a vaccine with the least vaccine adverse effects.

“People talk about how the US government might ask its Japanese counterpart to arrange a large quantity of the vaccine for Americans right before the 2003 war against Iraq, just in case biochemical weapons based on small pox were to be used against them,” says Tanaka.

But today people wonder if the glorious history of Japanese vaccine development might end because of the negative impact of the so-called “lost decades,” and the progress of globalization.

During Japan’s lost decades the multinationals, which are gigantic pharmaceutical companies, have developed and licensed new vaccines. The multinationals include Sanofi Pasteur, Merck, and GSK, or Glaxo-SmithKline.

Tanaka had a chance to talk with a former president of Sanofi Pasteur. In their talk, the former president said that the vaccination business carried a high degree of risk so pharmaceutical companies were trying to hedge such risk and keep the prices of the products down.

In order to achieve both the risk hedge and the cost-cutting, the companies had no choice but to make them far larger, meaning they must have the capacity to produce their vaccines in large volumes.

“Those companies have what they wanted to have. Global organizations such as WHO and UNICEF purchased in bulk various vaccines from these giant companies,” says Tanaka. “Then, their next target is us, the Japanese market.”

These pharmaceutical companies successfully applied for licensing of the Hib vaccine and PCV in 2007, and HPV vaccines in 2009, three of which were not locally developed in Japan during the lost decades.

According to Tanaka’s paper, after licensing, both pediatricians and gynecologists began to lobby for these vaccines to be included in Japanese national immunization programs. Due in part to the fact that the majority of members of the Japan Society of Hepatology supported introduction of universal vaccination with hepatitis B vaccine, the Japanese Medical Association issued a recommendation to expand the national immunization programs to include these antigens in 2010.

“Suddenly, with three new vaccines, the multinational companies have landed in Japan; it’s one of the most dramatic events the Japanese pharmaceutical market has ever experienced,” says Tanaka.

They continue to do thorough research work on the Japanese market because Japanese pharmaceutical prices have been kept very high, probably one of the highest in the world, due to a less competitive market controlled by leading domestic companies.

“For multinational companies that produce vaccines less expensively overseas and sell them at higher prices elsewhere, the high pharmaceutical prices mean high drug-price margins,” Tanaka adds. “And they might start wondering if they could dominate the high price vaccine market for about a million children every year.”

How could Japanese pharmaceutical companies compete with multinationals and hold on to their share of the local market? What if they lost a significant share and the entire Japanese vaccination practice had no choice but to rely on the multinationals?

“Remember the shortage of locally produced flu vaccines a couple years ago? We needed to buy them from overseas,” says Tanaka. “What if few reserve vaccines were sold to Japan? That’s a national security matter.”

But Tanaka believes that Japanese companies can compete with the multinationals if they merged into three or four companies and pursues strategies for gaining a share in the international market.

The lost decades have put Japan behind many high- and middle-income countries in terms of national vaccination programs. But the tradition and passion for better and safer new vaccines development has remained, says Tanaka.

A new HPV (human papillomavirus) vaccine, which the Japanese Infectious Disease Surveillance Center has been developing, exemplifies the tradition today.

“There are about 33 types of HPV, which are transmitted through sexual contact and may turn into precancerous lesions and invasive cancer. The vaccine that the multinationals applied for licensing in 2009 is effective for two types. The Japanese type is in the development stage and is expected to work for all types. So if the prototype is successfully completed and works as it should, I have no doubt that it will be the global standard” says Tanaka.

Time to move ahead again

In 2007, an outbreak of measles among high school and college students spread throughout the nation. The outbreak alarmed school administrators, who were reluctant to cooperate with the immunization program that dated from the late 1980s, when the influenza vaccine led to the end of mass immunization at schools. After the outbreak, immunization started to attract more attention from Japanese society and the media.

Many medical experts have already started to pay attention to redevelopment of national immunization programs since it was debated whether or not new vaccines against H5N1 influenza virus among poultry and humans could have been developed a few years earlier.

The so-called “Western type” hepatitis B, which was rarely reported in Japan, has become widespread among Japanese hepatitis B patients, a fact that has provided an opportunity for internal medicine specialists to pay closer attention to vaccinations.

Also, the fact that the multinationals applied for licensing of HPV vaccines in 2009 has also gained gynecologists’ attention.

Moreover, Japan’s younger generation has rationally accepted the benefits and the risks of vaccinations compared to previous generations, many of whom were intolerant of VAEs.

“Now is the time when a variety of stakeholders in vaccinations and the national immunization programs should consider a way of reconstructing a better social environment for the national vaccination programs and new locally developed vaccines,” says Tanaka.

“Also, related medical experts should place a priority on VAEs. As a result, at least, Japanese-translated versions of the latest international literature reviews on these issues should be published in the pertinent Japanese medical journals, since there is such a small database owing to the fact that they are all controlled by the ministry.”

The Japanese people face the daunting task of restructuring the national immunization program. It is a challenging goal we can achieve if all the stakeholders work to improve “the immunization literacy” of Japanese society as a whole.