Why Do Chinese Children Receive So Many Vaccine Injections? A Deep Dive into Combination Vaccines and Market Gaps

Editor’s Note: This article is reprinted from Occasionally Cured (ID: to-cure-sometimes), written by Li Shanshan, and republished with authorization by VCBeat.

Taking children for vaccinations is almost the first step in training parents to become “tiger dads” and “tiger moms.”

From the bewildered infant who only remembered to cry after the needle was withdrawn, rapidly growing into a brat who would burst into tears upon merely approaching the vaccination station—In the New York Times bestseller on vaccines, Immunity, the author mentions that she began researching vaccines during her pregnancy and, even by the time her child turned three, this arduous task remained far from complete.

I still remember that during the first nine months of my child’s life, we had to visit the vaccination clinic almost every month. Sometimes, when multiple vaccines were due simultaneously, the doctor would thoughtfully recommend administering one vaccine on the current visit and scheduling the remaining one or two for the following week. It was not uncommon to make several trips to the clinic within a single month.

Of course, I am not here to complain that children are receiving too many vaccines; rather, the number of trips required to vaccination clinics is simply excessive.

Flipping through the little green vaccination booklet for my child, I was surprised to find that despite the frequent shots, only vaccines included in the National Immunization Program had been administered. It did not include those Category II vaccines that experts unanimously recommend for families who can afford them—such as Haemophilus influenzae type b (Hib), pneumococcal, human papillomavirus (HPV, also known as the cervical cancer vaccine), and rotavirus vaccines. So, if a mother wishes to provide her child with greater protection, how many injections would be required? How could one possibly complete them all?

On the U.S. Centers for Disease Control and Prevention (CDC) website, I found their latest 2018 vaccination guidelines. An American child typically receives about 24 vaccine doses to prevent 16 infectious diseases. In contrast, under China’s Category I vaccine immunization schedule following the most recent expansion of its Expanded Program on Immunization in 2007, most Chinese children receive 22 doses to prevent 12 diseases. The United States prevents four more diseases than China with only two additional doses, which appears to be a modest difference.

However, upon closer examination, if we consider only the nine vaccines available in both China and the United States, the picture changes significantly.

Let’s put it this way: if there are two children, Han Meimei and Bob, Bob, who lives in the United States, would need only about 9 vaccinations to prevent the 9 core infectious diseases included in both China’s and the U.S.’s mandatory immunization programs from birth to 18 months of age, whereas Han Meimei would require 13 vaccinations.

In fact, Bob not only requires fewer injections but also gains protection against an additional pathogen that causes fatal meningitis and pneumonia—known as the “leading killer of children under five”—because he received an extra dose of the Haemophilus influenzae type b (Hib) vaccine. Among many senior pediatric infectious disease experts, Hib is considered virtually the most critical vaccine to include in national immunization programs.

If Han Meimei were to include this vaccine in her own vaccination schedule, she would need to receive four additional doses. As a result, the ratio of the number of injections required by Han Meimei and Bob would be 9:17, nearly doubling.

To prevent the same diseases, Han Meimei would need to receive eight more injections than Bob over an 18-month period. The primary reason is that Bob received a pentavalent vaccine based on the DTaP (diphtheria, tetanus, and acellular pertussis) combination, which requires four doses to complete the vaccination series. For each additional component integrated into a combination vaccine, a child can avoid four separate injections; therefore, the pentavalent vaccine reduces the total number of injections by eight compared to the trivalent vaccine.

On the U.S. FDA website, one can find information on six combination vaccines based on diphtheria, tetanus, and pertussis (DTaP) currently available in the U.S. market: two triple-component vaccines, two quadruple-component vaccines, and two pentavalent vaccines.

According to data released by the U.S. Health Resources and Services Administration, the pentavalent vaccine accounted for half of all diphtheria-tetanus-pertussis (DTP) vaccinations administered between 2006 and 2016.

Throughout 2017, among the vaccines approved and released in China, there was only one pentavalent vaccine—1.66 million doses of the pentavalent vaccine produced by Sanofi Pasteur—and only one quadrivalent vaccine—1.42 million doses of the quadrivalent vaccine produced by Beijing Minhai Biotechnology Co., Ltd. Based on China’s annual birth cohort of 20 million newborns, with each requiring four doses of the respective combination vaccines within the first 18 months of life, these combination vaccines were sufficient to cover only approximately 6% of infants.

From its approval for entry into China in 2011 until the end of 2017, the total import volume of Pentaxim (DTP-Hib-IPV), the only pentavalent vaccine available on the Chinese market and produced by Sanofi Pasteur, reached 11.5 million doses. In contrast, over the ten-year period from 2006 to 2016, nearly 120 million doses of pentavalent vaccine were administered to children in the United States.

As early as 1997, pentavalent vaccines began to be used in Canada and Europe. In 2011—14 years later—imported pentavalent vaccines were launched on the Chinese market.

Currently, a hexavalent vaccine containing diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B has also been officially launched in Europe.

Starting with cowpox for smallpox, humanity has recognized vaccines as a crucial tool in the prevention of infectious diseases and has become increasingly adept at utilizing this tool.

As research on infectious diseases advances, the list of vaccines continues to grow—a sign of progress that also brings considerable challenges due to the sheer number of vaccines available.

According to the U.S. CDC’s recommended immunization schedule, an infant needs to receive eight vaccines during the second month of life. Given the required intervals between vaccinations and the potential for adverse reactions in children, this task would be virtually impossible without combination vaccines.

At this point, combination vaccines capable of preventing multiple diseases emerged. As early as 1943, the diphtheria-tetanus-pertussis (DTP) triple vaccine was successfully developed, and it was officially launched on the market five years later. To date, the most important combination vaccines widely used in pediatric immunization—namely the quadrivalent, pentavalent, and hexavalent vaccines—have all been developed based on the DTP triple vaccine.

What is even more encouraging is that these novel combination vaccines have not increased the incidence of adverse reactions; rather, they have reduced it. A series of studies have found that when adverse reactions do occur with combination vaccines, their severity is not cumulative across all components but is instead determined by the component associated with the most pronounced adverse reactions. Furthermore, given that combination vaccines reduce the number of required inoculations, they significantly decrease the overall incidence of mild adverse events such as fever, rash, redness, swelling, and tenderness.

Data from the U.S. Vaccine Injury Compensation Program indicate that the rate of compensated injuries for the pentavalent vaccine, which combines diphtheria, tetanus, pertussis (DTP), and polio vaccines, is approximately 45 per million doses. In contrast, the compensation rates for standalone polio and DTP vaccines are approximately 124 per million and 145 per million doses, respectively. This means that the pentavalent vaccine has directly reduced the incidence of severe adverse reactions, including those causing disability, to one-quarter of the previous levels—a conclusion substantiated by a decade of data from an entire generation of American children.

A review article published in the Journal of Global Infectious Diseases in 2011 concluded that, overall, combination vaccines have a better safety profile, and the reduced number of injections effectively alleviates distress in modern infants.

The advent of this safe and convenient combination vaccine was first welcomed not by parents, but by epidemiologists eager to expand vaccination coverage.

The Children’s Vaccine Initiative (CVI), established in the 1990s, included in its founding plan the development of new combination (multivalent/multi-disease) vaccines “combined in novel ways” and their application in immunization programs.

Fewer injections, fewer visits to vaccination clinics, less pain for children, and less hassle for parents—all of which help boost parents’ willingness to take their children for vaccination. A U.S. research study showed that the use of pentavalent vaccines improved vaccine coverage compared with the use of multiple lower-valency vaccines containing the same antigens.

In its written response to us, Dr. Gauden Galea, WHO Representative in China, stated: “Combination vaccines indeed offer significant benefits to children participating in immunization programs and their parents. They reduce the number of injections required, thereby decreasing the frequency of visits to vaccination clinics and lowering the risk of missed doses, particularly for vaccines that require multiple administrations.”

Of course, in China, if parents wish to reduce the number of injections their children receive, they can opt for the pentavalent vaccine, which is available on a self-pay basis. At approximately RMB 700 per dose, the total cost for the four-dose series approaches RMB 3,000. On the surface, this appears to be an issue that money alone can resolve. However, frequent shortages often turn it into a problem that even money cannot solve.

Starting in January 2018, the pentavalent vaccine faced a nationwide shortage for eight months, rendering it unavailable for administration across China. Consequently, local Centers for Disease Control and Prevention (CDCs) were compelled to urgently issue alternative vaccination protocols for the pentavalent vaccine.

Why is there a shortage?

The most standard answer states that the pentavalent vaccine is an imported vaccine. Subsequently, media outlets began analyzing the production capacity of imported vaccines and the monopoly within China’s vaccine industry...

However, whether due to economic reasons or production capacity constraints for imported vaccines, the ultimate result is that only about 6% of children in China receive “premium” combination vaccines with a high degree of integration, such as quadrivalent and pentavalent vaccines. The vast majority of children from working-class families must make repeated visits to vaccination clinics for individual shots.

So, why are there not more combination vaccines available, why are there not more domestically produced combination vaccines to choose from, and why is there no domestically produced pentavalent vaccine that is not imported?

Perhaps this is where the problem lies.

China’s development of combination vaccines did not start too late.

Nine years after the pentavalent vaccine was launched in Europe, a quadrivalent vaccine developed by Wuhan Institute of Biological Products Co., Ltd. was approved in 2006. This vaccine combined diphtheria, tetanus, and pertussis (DTP) with hepatitis B. However, according to China’s immunization schedule, the DTP vaccine is administered at three months of age, while the hepatitis B vaccine must be given within 24 hours of birth. Due to this incompatibility with local vaccination practices, the combined vaccine was ultimately never marketed.

It remains unclear whether the discontinuation of the quadrivalent vaccine has adversely affected the enthusiasm of domestic companies in developing combination vaccines. When we consulted several industry insiders, almost all of them were aware of this quadrivalent vaccine.

Seven years later, in 2013, another quadrivalent vaccine developed by a domestic vaccine company was officially launched. This time, the antigens provided by the vaccine included those for diphtheria, tetanus, pertussis (DTP), and Haemophilus influenzae type b (Hib). To date, China does not have its own pentavalent vaccine.

An insider in the vaccine industry told us that pentavalent vaccines and other high-valency “combination vaccines” are, in a sense, landmark products signifying the development of a country’s vaccine industry.

Prior to 2015, China lacked its own inactivated poliovirus vaccine (IPV), which posed a significant obstacle to the development of domestically produced pentavalent vaccines based on diphtheria-tetanus-pertussis and polio components. However, even excluding the polio factor, China’s quadrivalent vaccines arrived late, with only one manufacturer entering the market. The reasons behind this delay are technical, economic, and political.

Technical factors stem from China’s outdated manufacturing processes for the diphtheria, pertussis, and tetanus (DPT) vaccine. This vaccine, which contains diphtheria, pertussis, and tetanus antigens, is typically administered to children at 3, 4, 5, and 18 months of age.

In 2012, an article titled “A Preliminary Study on the Current Status and R&D Trends of Pertussis Vaccines in China,” published in *Progress in Microbiology and Immunology*, bluntly stated: “China remains at the level of producing acellular pertussis vaccines using co-purification processes, lagging nearly 20 years behind developed countries in Europe and the United States.”

The gap is mainly reflected in the production process.

Currently, the more advanced and mainstream technology internationally involves separately purifying the diphtheria, pertussis, and tetanus vaccine components before combining them to formulate the DTaP vaccine. In contrast, all DTaP vaccines available in the Chinese market still employ a “one-pot” manufacturing process, wherein the three components are co-purified, resulting in an intertwined mixture. Consequently, these products exhibit lower purity and stability compared to component-purified counterparts.

One of the triggers for the Changsheng Biotechnology incident in the first half of this year was the discovery in October 2017 that hundreds of thousands of doses of diphtheria-tetanus-pertussis (DTP) vaccine failed to meet quality standards. In a report by Caixin Weekly, part of the reason for the “subpotent” DTP vaccines last year was attributed to the inferior quality and stability of DTP vaccines produced using co-purification methods.

In a sense, the co-purification process resembles the former “big pot” system, in which the rights and responsibilities of the three components are ill-defined. While this arrangement suffices for routine operations within their respective domains, conflicts become pronounced and difficulties multiply when attempting to develop more advanced combination vaccines through collaboration with external vaccine bulk substances.

Behind the technological backwardness lies a monopolized category of vaccine markets and a one-size-fits-all regulatory approach.

As the DTaP vaccine is a Category I vaccine subject to centralized national procurement, its procurement price—set in 2009 and never adjusted since—is merely RMB 3.4 per dose. This results in an excessively low profit margin, rendering it akin to “chicken ribs” (of little value yet reluctant to discard).

The major manufacturers of the diphtheria, tetanus, and pertussis (DTP) vaccine in the Chinese market are predominantly former state-owned biological product institutes that have undergone corporate restructuring, resulting in a highly monopolized industry.

Prior to 2018, the diphtheria-tetanus-pertussis (DTP) vaccines produced by Wuhan Institute of Biological Products and Changchun Changsheng Biotechnology—the two companies involved in the scandal—accounted for the majority of China’s DTP vaccine market.

It is evident that vaccine companies have little incentive to pursue technological upgrades for this class of vaccines, even though such advancements lay the foundation for further development of combination vaccines.

Here, there is neither a sufficiently open market nor substantial high profits, thereby lacking the impetus for technological advancement.

On the other hand, under current vaccine regulatory policies in China, two companies that produce different monovalent vaccines are prohibited from collaborating to manufacture combination vaccines, even if they belong to the same corporate group. This one-size-fits-all regulatory approach has ultimately resulted in a situation where companies with little interest in technologically upgrading their diphtheria-tetanus-pertussis (DTP) vaccines have become the only entities qualified to produce DTP-based combination vaccines.

Those who are qualified lack interest, while those interested are not qualified. For an emerging vaccine company to develop combination vaccines, it would mean having to redevelop all of its individual monovalent vaccines from scratch.

Vaccine companies that excel in capital markets naturally prefer new products with lower risk, greater ease of development, enhanced prestige, and stronger profit potential—such as the world’s first Ebola vaccine or the top-selling single-antigen vaccine globally. Yet few are committed to improving the manufacturing processes for traditional vaccines essential for every child, such as the diphtheria-tetanus-pertussis (DTP) vaccine.

“Chinese vaccine companies prefer to develop novel, newsworthy vaccines and show little interest in improving and enhancing existing manufacturing processes,” an industry insider told us.

The challenges faced by China’s DTaP-based combination vaccines bear a striking resemblance to the much-debated predicament of “Made in China.” It would be inaccurate to claim that we pay no attention to research and development; rather, within this focus, we often lack the patience and drive to lay a solid foundation. Consequently, we are more inclined to pursue seemingly glamorous strategies of “seizing the high ground” or myths of “overtaking on the bend.”

As the world’s largest vaccine consumer, China saw little change in the number of batch releases for combination vaccines from 2011 to 2016, with an average annual growth rate of 1.18%. This stagnation is largely at odds with the global trend toward the development of combination and multivalent vaccines.

In 2002, Gavi, the Vaccine Alliance, which focuses on ensuring that children in the poorest countries have access to vaccines, began efforts to introduce pentavalent vaccines into low-income countries.

By 2014, 149 countries worldwide had incorporated the pentavalent vaccine into their national immunization programs, and an additional 23 countries had adopted the hexavalent vaccine.

And as late as 2018, parents in China were still worried about whether the pentavalent vaccine, which requires fewer injections and carries lower risks, would continue to be in short supply.

In 2018, Changchun Changsheng received the largest fine in the history of China’s vaccine regulation—RMB 9.1 billion—following a major uproar caused by subpotent diphtheria-tetanus-pertussis (DTP) and rabies vaccines.

That same year, the legal representative of a private hospital was imprisoned for providing customers with 13-valent pneumococcal vaccines purchased from developed countries.