Profit considerations in vaccine safety-related events in China

Abstract

Objectives

China has made remarkable achievements in the field of immunization. However, several widespread vaccine safety-related events have recently received worldwide attention and reflect flaws in vaccine management. This study aimed to summarize vaccine safety-related events between 1985 and 2018 in China and analyze profit motives of these events.

Methods

Literature and media reviews were conducted to discover vaccine safety-related events. We developed a conceptual model with profit-related variables, and using information available from each event, we identified which profit-related variable was implicated, and how it related to the pursuit of higher profits.

Results

A total of 39 vaccine safety-related events were found in vaccine production, procurement, transportation, and daily management, along with adverse events following immunization (AEFIs). Overall, 90% (35/39) of the events could be classified as profit-driven. The motives of most events could be tied to one or more reasons, including decreasing costs among vaccine producers (67%, 26/39), reducing actual procurement price (67%, 26/39), and reducing costs of transportation and/or cold chain (24/39, 62%).

Conclusions

In order to deal with vaccine-related challenges, a more restrictive supervision system on vaccine production and more emergency preparedness, including health and risk communication strategies, for vaccine safety should be implemented.

1. INTRODUCTION

Vaccines are recognized as one of public health’s great accomplishments globally [1], with incidence and mortality associated with many vaccine-preventable diseases declining markedly in the past few decades [2]. The procurement and distribution of vaccines is key to controlling vaccine-preventable diseases [3]. Unfortunately this process can be opaque in many countries. Middle-income countries are an important location to study the evolution of vaccination programs. In aggregate, these countries have a huge birth cohort, meaning that the public health system is in charge of a large proportion of all vaccines administered worldwide. Middle income countries are also emerging as an important manufacturing hub of vaccines [4], yet their own vaccination programs can be quite expensive because they are not eligible for funding from programs like Gavi, the Vaccine Alliance, which negotiates down prices for vaccines and subsidizes their costs [5].

Vaccines are classified into two categories in China: category 1 vaccines, also known as mandatory or routine vaccines, are provided for free for all children; category 2 vaccines, also known as voluntary vaccines, are funded by out-of-pocket expenses from the parent [6]. Despite being on the World Health Organization’s Expanded Program on Immunization [7], some commonly used vaccines – such as rotavirus vaccine, Haemophilus influenzae type b vaccine, and pneumococcal vaccine – are category 2 vaccines in China. This pattern is seen in other middle-income countries as well; as a result of deficiencies in vaccine procurement, new vaccines have been adopted more slowly in middle-income countries than Gavi-supported low-income countries [5].

The two categories of vaccines in China have different supply channels. Category 1 vaccines are distributed from vaccine manufacturers first to the provincial Centers for Disease Control and Preventions (CDCs), next to sub-provincial CDCs, and lastly to thousands of vaccine providers all over the country. The distribution method of category 2 vaccines has changed several times. The legal channel for category 2 vaccines distribution and procurement was the same as Category 1 vaccines before June 2005. In accordance with the Administrative Regulations on the Circulation of Vaccines and Vaccination (version 2005) [8], between June 2005 and April 2016, qualified pharmaceutical wholesale companies were allowed to provide category 2 vaccines to any level of CDCs or to vaccine providers directly. After April 2016, the Chinese government promulgated a revised Administrative Regulations on the Circulation of Vaccines and Vaccination (version 2016) [9] with a new procurement method. Sub-provincial county-level CDCs must now purchase category 2 vaccines through a provincial group-purchasing organization platform and distribute vaccines to vaccine providers. Since 2016, pharmaceutical wholesale companies are not allowed to sell vaccines directly to any level of CDC or vaccination provider. The newest set of regulations also provides additional guidance on cold chain logistics.

The pricing method for category 2 vaccines has also changed during this time period. Before 2016, CDCs and vaccine providers were allowed to offer category 2 vaccines with distributor markups. After April 2016, fixed service fees per dose were charged instead of markups.

The Chinese National Vaccine Regulatory system passed assessments twice by the World Health Organization (WHO) in 2011 and 2014, indicating that Chinese vaccine regulatory oversight meets international standards [4]. Unfortunately, several vaccine safety-related events have recently occurred and received global attention. In March 2016, an illegal vaccine scandal in Shandong was widely shared throughout social media, and involved 24 provinces and municipalities, 25 types of category 2 vaccines worth $88 million, in which the vaccines were neither adequately refrigerated nor transported in approved conditions [10]. In July 2018, Changsheng Biotechnology, the second largest producer of rabies vaccines in China, was found to have faked records in the process of vaccine production starting in January 2014 [11].

These events have the potential to diminish the public’s confidence in vaccine safety and the public health system as a whole [12]. These events also shed light on the difficulties China has in managing its vaccination program and in developing the infrastructure to support both mandatory and voluntary vaccines. Yet there have been few comprehensive reports about vaccine safety related-events in China. Thus, this study aimed to describe vaccine safety-related events in the past few decades in China, and to explain the motives of stakeholders.

2. METHODS

2.1. Literature and media reviews

We carried out a systematic review of vaccine safety-related events in Chinese databases (including CNKI, CBM, WanFang and China Core Newspapers Full-text Database) and in English databases (including Medline, EBSCO, and Pubmed). The reported time of these events was confined to between 1985 and 30 September 2018. The web search engines Baidu and Bing were additionally used to make a news media review. The search terms were: (vaccine OR category 2 vaccine) AND (management OR procurement) AND (scandal OR event OR fake OR problem OR safety). Chinese or English was used depending on the search engine.

In order to be included in this study, the event had to meet the following inclusion criteria. The event must:

• be in China;

• have an explicit record of time, place, persons, company or institution involved;

• have had vaccine-related hazards, potential hazards or suspected hazards; and

• had an investigation report from authorities.

Events were excluded if they were:

• individual media reports without authentication (i.e., no official confirmation of event);

• a discussion of events in studies and articles without specific details;

• only an individual case with a known adverse event following immunization (AEFI); or

• purely economic problems without direct evidence of an impact on vaccine safety, such as bribery or irregular charges.

2.2. Profit-driven models

According to reports from two major vaccine scandals in China [10,11], pursuing higher profits was one of the most important reasons of the events. Additionally, other public health problems in China and other locations have derived from profit motives, and this has been commonly seen with prescription antibiotics [13–15]. Accordingly, we analyzed profit motives using the methods from Profit Driven Business Analytics, which posits that profit-driven business analytics can be used for better decision making – that is, business decisions rely on maximizing net profits, returns, payoff, or value. The incurred returns may stem from a gain in efficiency, lower costs or losses, and additional sales [16]. We used this approach as a theoretical basis to qualitatively explore profit motives of the events. A description of each variable is provided in Table 1.

Table 1.

Variables in the model and their descriptions.

Variable	Description	Profit-driven direction	Examples of profit-driven behaviors
NP	Net profit of stakeholders	↑
D	Quantity of specific type of vaccine in procurement	↑	Increase coverage, increase completion rate, give booster shots, organize vaccination in groups, introduce new vaccines, expand eligible age range, use non-vaccine product
S	Quantity of specific type of vaccine unsold	↓	Reduce wastage of vaccines by selling expired or near expired vaccines, faking the date of production
R	Distributor mark-up rate (%)	↑	Increase mark-up rate
P	Unit price of vaccine (nominal price)	↑	Increase nominal procurement price
P′	Unit price of vaccine (actual price)	↓	Reduce actual procurement price
U	Unit price of vaccination service	↑	Increase unit price of vaccination service, increase type of charge, etc.
N	Quantity of vaccination service	↑	Increase coverage, increase completion rate of schedule, give booster shots, organize immunization in groups, introduce new vaccines, expand eligible age range
C	Cost of production or immunization service (including costs of transportation, storage, personnel, education and promotion, necessary materials, etc.)	↓	Reduce necessary cost reasonably or illegally, conserve the cost of raw material (for example, antigen), reduce cold chain costs

2.3. Profit-related factors

According to the regulations (version 2005) [8], the income for vaccine distributors came from the price differences in procurement and the allowable distributor makeup rate (R), which varied 5%−25% across provinces [17]. The value of R could be different in each step during the process of circulation from vaccine producer to vaccination provider. The direct costs (C) for vaccine distributors came from the procurement of vaccines from vaccine producers or other channels and the cost of transportation, storage and personnel. The incomes for vaccine providers came from the price differences between procurement from vaccine distributors and sales from parents, and the charge of immunization service (U). The CDC could be responsible for vaccine distribution and vaccination simultaneously or just offer the service of vaccine distribution in select cities.

From the investigation reports of some events, there were two kinds of unit prices of vaccine during procurement [10]. One was nominal price (P), which was published reported to regulators. Another was actual price (P′) which was the real price in the procurement. Thus, although these two kinds of prices were equal in most CDC and vaccine providers, we distinguished them in the model as two variables.

For both vaccine distributors and providers, wastage was a common problem due to expiration of vaccines and other reasons. And the quantity of vaccine were calculated as the difference of the quantity of specific type of vaccine in procurement (D) and quantity of specific type of vaccine unsold (S).

According to the regulations (version 2016), all category 2 vaccines must be procured through provincial group purchasing organizations, and price differences are forbidden. For the vaccine providers, legal income comes from a fixed service fee per dose (U) which varies from 20 to 30 RMB (about $3-$4) across provinces [18,19].

For vaccine producers, income and cost could include research, depreciation, leverage, investments, and direct and indirect costs. In our study, we only discuss the direct income of vaccine sales and cost of vaccine production because most information on other sources could not be found from open sources.

Because the subsequent use of net profit was not reported in any cases, secondary profit was not involved in this study. In this linear model, net profit was chosen as the outcome measure, and its components were analyzed by stakeholder. The net profit changed in accordance with variables in the model. For any stakeholders, pursuing higher net profit was a better decision.

We qualitatively analyzed the potential for profits for various stakeholders by adding different sources of income and subtracting costs (Table 2). These equations were qualitatively used to describe which profit-related factor was present in the event. At least three types of stakeholders were involved in the events: vaccine producers, distributors and providers. The income and cost of different stakeholders in the service of immunization were analyzed, and the component of net profit (NP) was expressed as the difference between income and cost. Only direct income and cost of circulation and vaccination were considered in this study; indirect costs and secondary investments were not included.

Table 2.

Profit-driven model for different stakeholders.

Stakeholders	Income of vaccine sales	Income of vaccination service	Cost of vaccine procurement	Cost in the process of vaccine production and/or immunization service
Vaccine producer	$\sum _{i=1}^a(D-S)i\times Pi$	N/A	N/A	$\sum _{\mathrm{t}=1}^{d}C\mathrm{t}$
Vaccine distributor	$\sum _{i=1}^a(D-S)i\times Pi\times (1+Ri)$	N/A	$\sum _{\mathrm{k}=1}^{c}D\mathrm{k}\times P\mathrm{\prime }\mathrm{k}$	$\sum _{\mathrm{t}=1}^{d}C\mathrm{t}$
Vaccine provider	$\sum _{i=1}^a(D-S)i\times Pi\times (1+Ri)$	$\sum _{\mathrm{j}=1}^{b}Nj\times \mathrm{U}$	$\sum _{\mathrm{k}=1}^{c}D\mathrm{k}\times P\mathrm{\prime }\mathrm{k}$	$\sum _{\mathrm{t}=1}^{d}C\mathrm{t}$

For vaccine producers, the direct income of vaccine sales could be calculated as the sum of sales from each individual vaccine product, expressed as the unit price (Pi) multiplied by the sales volume. Sales volume was constant across the three stakeholders; the sales volume could be expressed as the total number of vaccines coming from the process of production or procurement (D) minus the number of vaccines unsold (S). An example of vaccine producers manipulating this equation would be vaccine producers selling expired vaccines to expand their sales volume.

Vaccine distributors and vaccine providers could sell the vaccines at a higher price, although the amount distributors could mark-up varied over time according to regulations. Overall, the cost of vaccine procurement was opaque, because the actual procurement price could vary across vaccine distributors.

For vaccine providers, they could also earn profit from the vaccines supplied for public. This could be expressed as the unit price (U) multiplied by the quantity of vaccines sold (N).

Vaccine procurement includes other direct costs, including costs of transportation, storage, personnel, education and promotion, necessary materials, etc.

Net profit of stakeholders (NP) was calculated by subtracting total expenses including cost of vaccine procurement (related variables: D,P′) and cost in the process of vaccine production and/or immunization service (related variable: C) from total revenue including the income of vaccine sales (related variables: D, S, P, R) and/or income of vaccination service (related variables: N, U). According to Regulations (version 2005), the net profit of stakeholders could be summarized as equation 1.

$$NP=\sum _{i=1}^a(D-S)i*Pi*(1+Ri)+\sum _{\mathrm{j}=1}^{b}Nj*\mathrm{U}-\sum _{\mathrm{k}=1}^{c}Dk*P^{\mathrm{\prime }}\mathrm{k}-\sum _{\mathrm{t}=1}^{d}C\mathrm{t}$$ (1)

This model was suitable for different stakeholders in the field of immunization service, as shown in Table 2. The business modes of vaccine distributors and providers were similar. The differences existed in the process of income of vaccination service.

According to regulations (version 2016), the net profit of vaccine distributors and providers could be simplified as equation 2. In equation 2, R=0, P= P′, and U is set as a constant value at the provincial level.

$$NP=\sum _{j=1}^{b}Nj*U-\sum _{\mathrm{t}=1}^{d}C\mathrm{t}$$ (2)

And for vaccine producers, the mode of net profit did not change, as showed in equation 3.

$$NP=\sum _{i=1}^a(D-S)i*Pi-\sum _{\mathrm{t}=1}^{d}C\mathrm{t}$$ (3)

2.4. Use of the model

The model was used as an explanatory tool to explain whether the vaccine safety-related events were profit-driven and to help understand which process was problematic. If the posited reason of one single event matched the theoretical extrapolation of the model, i.e., if the behavior of any stakeholders involved in the event was consistent with the theoretical profit-driven change of any variables of the model, this event would be classified as profit-driven. Otherwise, the event would be classified as a non-profit-driven. We defined a profit-driven event as one for which there was an obvious financial incentive for vaccine quality or safety to be impacted. The prevalence of each profit-driven factor was calculated as the number of events which could be tied to that profit-driven factor, divided by the total number of events. Each event could be tied to one or more profit-driven factor. The specific profit motives for vaccine producers, distributors, and/or providers were also specified for each event based on information available in public reports.

3. RESULTS

3.1. Vaccine safety-related events reported in China

A total of 83 potentially eligible studies or news items were identified in database searches; 5 were ineligible and 39 were excluded after full text screen, leaving 39 vaccine safety-related events reported between 2003 and 2018 from public media and regulators (Figure 1). Not all events had AEFIs: 23 did not, 16 had an identified AEFI, which may have included deaths, and 3 had adverse events originally suspected to be related to an immunization event, but later ruled to not be causally linked to immunization by an official investigation. The distribution of these events covered the whole chain of immunization service including vaccine production, procurement, transportation, vaccination and AEFI. We divided the timeline into three periods relative to changes in regulations in 2005 and 2016, and summarized the key problems and impacts of similar events in Table 3.

Figure 1:

Studies or news item selection

Table 3.

Vaccine safety-related events reported in China.

Event ID	Reference	Reference	Description	Consequences	Vaccines involved	Vaccine category	Vaccine producer	Vaccine distributor	Vaccine provider
	Before 1 June 2005	Before 1 June 2005
A1	Jing et al (2004) [20]	Jing et al (2004) [20]	12,000 boxes of fake rabies vaccine were produced.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer
A2	Jinling News (2004) [21]	Jinling News (2004) [21]	A child died of rabies after receiving a fake rabies vaccine in May 2004.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Private clinic
A3	Anhui News (2004) [22]	Anhui News (2004) [22]	One person died of rabies after receiving a fake rabies vaccine in June 2004.	One death due to rabies disease	Rabies vaccine	2	Unclear	Illegal private vaccine distributor	Private clinic
A4	Dai (2004) [23]	Dai (2004) [23]	6,000 vaccine doses were distributed by a vaccine distributor without certification. About 600 children received these illegal vaccines.	No AEFIs reported	Oral polio vaccine, varicella vaccine and other unmentioned vaccines	1 and 2		Illegal private vaccine distributor (also in #B2)	Maternal and child care service center
	1 June 2005 to 13 April 2016	1 June 2005 to 13 April 2016
B1	Xinhua News Daily (2006) [24]	Xinhua News Daily (2006) [24]	468 doses of fake rabies vaccine were made with distilled water	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B2	Bai (2006) [25]	Bai (2006) [25]	Vaccines improperly administered to a group. About 2,500 students received a hepatitis A vaccine procured from an illegal private vaccine distributor.	One girl died and approximately 100 hospitalizations of children due to AEFIs	Hepatitis A vaccine	2		Illegal private vaccine distributor (also in event A4)	Rural health center
B3	China Food and Drug Administration (2007) [26]	China Food and Drug Administration (2007) [26]	5,123 doses of fake rabies vaccine were made with distilled water.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B4	Xinhua News (2007) [27]	Xinhua News (2007) [27]	10,000 doses of fake rabies vaccine were made with distilled water.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic and several rural doctors
B5	Sina News (2007) [28]	Sina News (2007) [28]	50,000 doses of fake rabies vaccine were made with distilled water.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B6	Cheng (2007) [29]	Cheng (2007) [29]	45,000 doses of fake rabies vaccine were produced.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer
B7	Wu (2007) [30]	Wu (2007) [30]	One person died of rabies after receiving a fake rabies vaccine in 2007.	One death due to rabies disease	Rabies vaccine	2		Illegal private vaccine distributor	Rural clinic
B8	Orient Today (2007) [31]	Orient Today (2007) [31]	Two persons died of rabies after receiving a fake rabies vaccine 2007.	Two deaths in one family due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic
B9	Yongfeng (2008) [32]	Yongfeng (2008) [32]	180 doses of fake rabies vaccine were made with distilled water.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B10	Sohu News (2008) [33]	Sohu News (2008) [33]	One person died of rabies after receiving a fake rabies vaccine in 2008.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic
B11	Hao (2009) [34]	Hao (2009) [34]	One person died of rabies after receiving a fake rabies vaccine in 2009.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic
B12	Lu et al (2009) [35]	Lu et al (2009) [35]	One person died of rabies after receiving a fake rabies vaccine in 2009.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Urban public clinic
B13	Cui (2009) [36]	Cui (2009) [36]	Substandard rabies vaccines were produced. Illegal material was added to 11 lots of rabies vaccines (about 360,200 doses), to reduce costs.	No deaths reported	Rabies vaccine	2	Dalian Jingang Andi Biological Products Co., Ltd.
B14	Sohu News (2010) [37]	Sohu News (2010) [37]	Substandard rabies vaccines were produced. 4 lots of vaccine were involved (about 180,000 doses), which did not induce adequate protection.	No deaths reported	Rabies vaccine	2	Jiangsu Yanshen Biotechnology Co., Ltd.
B15	Sohu News (2010) [38]	Sohu News (2010) [38]	Substandard rabies vaccines produced from biological companies. 3 lots of vaccine (about 35,800 doses) were involved, which did not induce adequate protection.	No deaths reported	Rabies vaccine	2	Hebei Fuer Biological Pharmaceutical Co., Ltd.
B16	Wang (2010) [39]	Wang (2010) [39]	One person died of rabies after receiving a fake rabies vaccine in 2009.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B17	Xibuwang (2010) [40]	Xibuwang (2010) [40]	One person died of rabies after receiving a fake rabies vaccine in 2010.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic
B18	Qin (2010) [41]	Qin (2010) [41]	Some children who were not in the eligible age range received the vaccine.	13 hospitalizations after hepatitis A vaccine immunization in 15 villages.	Hepatitis A vaccine	1 and 2			One rural physician
B19	Juan (2010) [42]	Juan (2010) [42]	Vaccines were suspected to be linked with severe AEFIs.	Almost 100 children with suspected severe AEFIs were reported by media, however, an official investigation report found no causal linkage	Japanese encephalitis vaccine, oral polio vaccine and other unmentioned vaccines	1 and 2			Provincial-level clinic
B20	Xu et al (2011) [43]	Xu et al (2011) [43]	One person died of rabies after receiving a fake rabies vaccine in 2010.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Private clinic
B21	China Police (2012) [44]	China Police (2012) [44]	19,000 doses of fake rabies vaccine were made with saline solution in 2011.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B22	Legal Daily (2012) [45]	Legal Daily (2012) [45]	About 19,000 doses of fake rabies vaccine were made with saline solution in 2012.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B23	Xiandai Jinbao (2012) [46]	Xiandai Jinbao (2012) [46]	1,200 doses of fake rabies vaccines made with distilled water in 2012.	No deaths reported	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor
B24	Qiluwanbao (2012) [47]	Qiluwanbao (2012) [47]	Vaccines were illegally procured, inadequately refrigerated, and transported in unapproved conditions from 2005 to 2012. 42,494 doses of category 2 vaccines worth 120 million RMB ($18m) were involved.	No AEFIs or and deaths reported	Almost all category 2 vaccines	2		Illegal private vaccine distributor	CDCs and clinics from ≥5 provinces
B25	Legal Daily (2014) [48]	Legal Daily (2014) [48]	One person died of rabies after receiving a fake rabies vaccine in 2014.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic
B26	Guo et al (2015) [49]	Guo et al (2015) [49]	Disinfectant was marketed as a vaccine.	No AEFIs were reported	Disinfectant (declared as hand, foot, and mouth disease vaccine in the materials for parents)	2			CDCs and clinics from ≥3 provinces
B27	Cao (2015) [50]	Cao (2015) [50]	Therapeutic biologics were marketed as a vaccine.	Suspected linkage with Kawasaki disease	Lantigen B, a therapeutic biologic but not officially registered as a vaccine in China	2			CDCs and clinics from ≥9 provinces
B28	Henan TV (2015) [51]	Henan TV (2015) [51]	About 400 children were reported to have received expired vaccines.	No AEFIs reported	Diphtheria-tetanus-acellular pertussis vaccine and other unmentioned vaccines	1 and 2			Rural clinic
B29	Yue (2016) [52]	Yue (2016) [52]	One person died of rabies after receiving a fake rabies vaccine in 2016.	One death due to rabies disease	Rabies vaccine	2	Fake rabies vaccine producer	Illegal private vaccine distributor	Rural clinic
B30	BBC (2016) [10]	BBC (2016) [10]	Vaccines were illegally procured, inadequately refrigerated, and transported in unapproved conditions from 2010 to 2016. 25 types of category 2 vaccines worth $88 million were involved.	No AEFIs or and deaths reported	25 different category 2 vaccines	2		Illegal private vaccine distributor	CDCs and clinics from 24 provinces
B31	Yu et al (2016) [53]	Yu et al (2016) [53]	Vaccines were suspected to be linked with severe AEFIs.	21 infant deaths were reported after hepatitis B vaccination, however, an official investigation report found no causal linkage	Hepatitis B vaccine	1	Shenzhen Kangtai Biological Products Co., Ltd, is the the main suspect
	13 April 2016 to 30 September 2018	13 April 2016 to 30 September 2018
C1	China FDA (2017) [54]	China FDA (2017) [54]	3 lots of DTaP vaccine were reported due to insufficient potency.	No AEFIs reported	Diphtheria-tetanus-acellular pertussis vaccine	1	Wuhan Institute of Biological Products and Changchun Changsheng Biotechnology Co., Ltd.
C2	Dami (2018) [55]	Dami (2018) [55]	4 lots of influenza vaccine were reported due to insufficient potency.	No AEFIs reported	Influenza vaccine	2	Sanofi Pasteur Biological Products Co., Ltd.
C3	Sohu News (2018) [56]	Sohu News (2018) [56]	Vaccines were illegally procured from 2015 to 2016. 13,000 doses of unregistered vaccines were smuggled from abroad.	No AEFIs reported	13-valent pneumococcal conjugate vaccine	2			Shanghai Meihua Medical Group
C4	Murphy (2018) [11]	Murphy (2018) [11]	Substandard rabies vaccines were produced. Records about production were faked from 2014 to 2018.	No AEFIs reported	Rabies vaccine	2	Changchun Changsheng Biotechnology Co., Ltd.

In general, there were three main types of events in the process of vaccine production. One was counterfeit rabies vaccines produced by illegal producers who sold saline solution or distilled water as a vaccine (n=22). The second was substandard rabies vaccines produced by companies violating Good Manufacturing Practice (GMP) (n=4). The third was insufficient potency of vaccines related to occasional accidents in the process of vaccine production (n=2).

Illegal procurement were the crucial problems in the processes of procurement and transportation (n=4), along with inadequate storage (n=2). Although only qualified pharmaceutical wholesale companies were franchised to distribute category 2 vaccines, some unqualified companies and individuals who offered less expensive vaccines were involved in this process. Additionally, to cut costs, vaccines in some circumstances were stored in room temperature without any refrigeration equipment (events B24, C4).

Other events could be categorized as following: suspected AEFI in group (n=2), administration of vaccines in those ineligible to be vaccinated (n=2), falsely portraying therapeutic biologics or disinfectants as vaccines (n=2), and using expired vaccines (n=1).

Some cases did not have a clear conclusion. In event B26, therapeutic biologics were misrepresented as a preventive vaccine and some children were diagnosed with Kawasaki disease after the usage of the product. However, the relationship between the adverse outcomes and vaccination was unclear. In event B27, disinfectants were branded as vaccines for Hand, Foot, and Mouth Disease, yet the effect of the vaccines on the children was unreported. In event B28, about 400 children were reported to have been administered expired vaccines, in which a lot of severe AEFI cases were identified and then linked with vaccination. According to the local government’s investigation report, several individuals associated with the event were punished. However, the investigation report denied that the vaccines were expired.

In event C3, vaccines from abroad were used in China, even though the vaccine had not undergone clinical trials of safety within China [56], as is required for any vaccine on the market in China.

3.2. Prevalence of profit-related factors

Overall, 90% (35/39) of the events could be classified as profit-driven, and, among the profit-driven events, there were ten different scenarios of how profit was involved (Table 4). The motives of most events could be tied to one or more reasons, including decreasing costs among vaccine producers (67%, 26/39), reducing actual procurement price (67%, 26/39), and reducing costs of transportation and/or cold chain (24/39, 62%). Less common were the drive to increase quantity of vaccines in procurement among vaccine providers (4/39, 10%), among vaccine distributors (4/39, 10%), or among vaccine providers (5/39, 13%), or vaccine providers increasing the quantity of services provided (4/39, 10%).

Table 4.

Profit-driven considerations for 39 vaccine safety-related events in China.

Events’ ID	Number of events	Stakeholders’ considerations
		Vaccine producer	Vaccine distributor	Vaccine provider
A1-A3, B1, B3-B12, B16, B17, B20-B23, B25, B29	22	C↓	none	P′↓
A4	1	none	D↑	P′↓
B13-B15	3	C↓,D↑	none	none
B24, B30	2	none	C↓	P′↓
B2	1	none	D↑	P′↓,D↑,N↑,R↑
B26, B27	2	none	D↑	D↑,N↑
B18	1	none	none	D↑,N↑
B28	1	none	none	C↓
B19, B31, C1, C2	4	none	none	none
C3	1	none	none	D↑
C4	1	C↓,D↑,S↓	none	none

4. DISCUSSION

Although immunization is regarded as one of the most effective and safest interventions to prevent and control vaccine preventable diseases, vaccine safety continues to face challenges globally [57]. Vaccine safety requires monitoring all aspects and process of the immunization service - such as vaccine quality, storage, transportation, and injection, and does not only refer to AEFIs [58].

Balancing profits and risks is crucial within health care. The American Public Health Association has noted that national health is not well served by the unchecked growth of a for-profit health care market [59]. In China, the profit from the vaccines supplements public health funding, and without them, the routine operation of the CDC and vaccine provider may face direct economic difficulties in many regions of China. This may be the intrinsic reason that so many public health institutions were involved in these events.

Authorities have made repeated efforts to deal with the problems in the management of vaccines in China. Two major revisions occurred in 2005 and 2016 to the Administrative Regulations ono the Circulation of Vaccines and Vaccination. These revisions were issued to deal with existing challenges in the procurement of category 2 vaccines. The types of vaccine safety-related events changed after these revisions went into effect. Before 2005, the market of category 2 vaccines was relatively limited and profit-based challenges were concentrated in vaccine procurement. Between 2005 and 2016, the market of category 2 vaccines expanded and profit-based challenges became more concentrated in the processes of vaccine production, procurement, and service. Since 2016, there have been fewer challenges in procurement and vaccination service, but problems still exist with vaccine production. Overall the profit models helped us to understand why certain profit-related factors occurred at what point in time, and have identified limitations in the revisions.

In order to lower the procurement price, competition was introduced into the procurement of category 2 vaccines by marketization. Companies were allowed to offer vaccines directly to CDC and vaccine providers with the implementation of regulations (2005 version) [8]. However, the outcome was not in line with prior expectations, which was to lower the price of Category 2 vaccine for public. However, what actually happened was the rise of the nominal procurement price which was used for selling price for public and the decline of the actual procurement price, according to the investigation reports. This discrepancy may have resulted because nominal procurement price was used as the base price and stakeholders could gain more profit from the lower actual procurement price. Without effective supervision, many individuals without certification participated into the process of vaccine supply, and these illegal distributors could offer much cheaper vaccines by cutting off the cost of cold chain in storage. Without appropriate storage, it would be difficult to guarantee the safety and effectiveness of the vaccine. This was the key risk in the globally reported Shandong vaccine scandal [10].

Soon after the report of Shandong vaccine scandal in 2016, a revised Administrative Regulations on the Circulation of Vaccines and Vaccination (2016 version) was published [9]. In the aftermath, the characteristics of vaccine safety-related events have changed significantly. Ever since procurement was limited to the CDC system, and detailed policies about maintaining the cold chain were promulgated, no event similar to the Shandong illegal vaccine event has been reported, which indicates that the revised regulations have had some effectiveness. As shown in the equation 2, the profit from price disparities in the process of vaccine procurement for CDCs and vaccine providers was forbidden and the only legal income is the service fee per dose which is now a fixed value in each province in China. This method effectively regulated the process of procurement, however, an underlying question remains whether the charge of service is enough to motivate public health institutions to offer category 2 vaccines.

Equation 3 predicts that the business mode of vaccine producers will not change and similar events are likely to re-occur. In July 2018, problems in the production of rabies vaccine occurred which were similar to previous events, which validated this hypothesis [11]. Although the National Vaccine Regulatory system passed assessments of WHO, a more sensitive supervision system should be implemented to focus on the high risk process of vaccine production, build a high-risk product list, and accelerate the speed of recall [60]. Vaccine safety can be improved in China for vaccine producers (ensuring Good Manufacturing Practice (GMP) controls, instituting fast recalls and fast path of registration for new vaccine products), vaccine distributors (maintaining procurement through the CDC system, monitoring cold chain system), and vaccine providers (improving immunization information systems, providing training and exams on vaccine safety). After a vaccine safety- or quality-related event has occurred, communication with the public is key. The Chinese President Xi Jinping addressed his country after one such scandal [61], and high profile figures talking to the public about the event can be important to allay concerns. Messages should be open, transparent, timely, acknowledge uncertainty, and can provide apologies as appropriate [62,63].

Improving the cold chain supply is also key to reducing the number of these vaccine safety- or quality-related events. Many vaccines require refrigeration between 2°C and 8°C, and some, like varicella or measles-containing vaccines need to be frozen between −15°C and −5°C [64]. Traditional temperature-monitoring devices may miss deviations from acceptable temperature ranges. One study in Connecticut found 14.05% of total vaccine doses were exposed to potentially damaging temperatures. But of 66 events recorded, only 1 was identified with a traditional temperature-monitoring device [65]. The use of technologies such as visual freeze indicators on vaccine supplies could be one way for vaccine distributors and providers to ensure the vaccine supply adheres to rigorous temperature controls.

The nature of vaccine safety-related events are distinct between China and high-income countries, such as the US. The main kinds of events reported recently in US have been AEFIs and possible contaminants in the process of vaccine production. Some severe outcomes have been linked to immunization, such as rotavirus vaccination with intussusception [66]. Some events happened in the process of vaccine production, such as a recall of Hib vaccines due to concerns about potential contamination with B. cereus [67], and recall of HPV vaccines due to concerns that a small number of vials might have contained glass particles due to breakage [68]. In this review, the four events from China that were not profit-driven were similar to those in the US, and they may be a larger proportion of overall vaccine quality-related events in China in the future as China develops economically and increases regulations. Various organizations have developed pooled procurement mechanisms which may limit problems in vaccine quality-related events being tied to procurement in other countries. The Pan American Health Organization (PAHO) Revolving Fund and the UNICEF Supply Division operate such programs [69]. These procurement programs may be particularly suitable to smaller countries with limited resources [70].

The large number of vaccine-safety related events have weakened the public’s confidence in vaccination and may fuel anti-vaccine movements in China [71]. The Chinese government’s response is crucial, especially in a society with widespread social media use. According to a survey launched by the China National CDC, one month after the event of hepatitis B vaccine and infant death in 2013 [53], the immunization rate of hepatitis B vaccine dropped by 30% in ten provinces in China, and those of other routine vaccines dropped by 15%. 80% of the parents in this survey held the view that they did not trust the findings from the government [50]. We suggest more emergency preparedness for vaccine safety, which may include the improvement of risk communication skill to the public, preparation of reader-friendly health education material, and integrating social media into emergency-preparedness and response efforts.

To the best of our knowledge, our study was the first one to employ a profit-driven model [72] to interpret the root of the vaccine safety-related events in China. There were several limitations in our study. The inclusion of the events is likely very incomplete because maybe some events were not revealed to the public, and older events would not have been reported on the internet. However, the likelihood of missing significant events including many individuals within the past fifteen years is reduced because of social media and the presence of online news sources. The second limitation was that profit might be one of the common and key motivations in these diverse events but not the only reason. Other reasons could include not enough supervisory power, lack of useful tools to record the temperature during the whole cold chain, insufficient supply of some certain imported products, and lack of training in adverse events following immunization. The third limitation which was also the most difficult one to solve was that this model could only be used as a qualitative, explanatory tool. It was not able to answer how much profit is enough to drive a stakeholder to disobey regulations and which variables are more important in the decision-making process. The stakeholders did not publicly publish profits, and the information released from the investigation reports were limited. Thus, it was impossible for us to calculate the robustness, goodness of fit or quality of this model. It was also impossible for us to estimate the cutoff value for the stakeholders to make the decision to obey or disobey the rules because the profit of the stakeholders gained from their misdeeds had a tremendous range, from thousands to millions of RMB [10,21]. Future quantitative studies might also consider indirect costs. More detailed data and factors should be made publicly available to answer these questions.

Nevertheless, there were also some advantages to use the model. First of all, from our study, we could see that vaccine safety-related events in China were diverse, enormously influential, long-lasting, and mainly related to category 2 vaccines (voluntary and self-paid vaccines). Within the same immunization service system, the disparity between the great achievements of category 1 vaccines and the frequent occurrence of vaccine safety-related events in category 2 vaccines indicate that the differences of procurement and supply may play key roles. Using the model, it was easier to understand that the main motivations of most of the events were similar and remained unchanged during the past decades. According to the results, we could classify those vaccine safety-related vaccines into two types. One was profit-driven and the other was not. This differentiation could help the regulators and public to understand what the main challenges are, and what could happen in the future. Secondly, the model helped us to draw a list of high risk processes and behaviors. It would help the regulators to pay more attention to those high risk behaviors, particularly for category 2 vaccines. Thirdly, it was easier to interpret some paradoxes. For instance, the introduction of market–oriented competition could lower down the procurement price in theory, however, in this model, it could decrease net profit. Thus, the nominal price would not drop and the introduction of marketization in the process of procurement would not lighten the cost burden for parents. Additionally, there are regulations related to cold chain management. However, in order to reduce costs, some vaccine distributors chose to store the vaccine at room temperature. In this model, it was easier to see that breaking the cold chain could increase the net profit of the vaccine distributor. In general, the profit-driven model helped to understand why and how the events happened.

Similar profit-driven behavior was reported in the field of profit-driven overuse of injections and infusions in China’s market-based healthcare system, which can explain the overuse of antibiotics to treat the common cold [13]. The experience and lessons of the usage of category 2 vaccines in past decades in China is unique [73] but can provide a blueprint for other low and middle income countries on how to manage their country’s vaccination system. For example, privatization of procurement should be accompanied by adequate supervision, and problems with vaccine producers, deliverers, and providers should be addressed ahead of time. Vaccine safety-related events are not just unique to China. Media reports of such events have surfaced from other countries, including Indonesia [74] and the Philippines [75] in recent years. Indonesia responded to fake vaccines being passed off as polio and hepatitis B vaccines by arresting the culprits, and the Food and Drug Administration (FDA) of the Philippines worked to quarantine purportedly fake rabies vaccine supplies and warn medical professionals.

5. Conclusions

China’s successes in immunization are remarkable [4,76]; however, the flaws in the system should also be faced objectively. The value of this study was to summarize and reflect upon problems in the field of vaccine safety in China. An profit-driven business analytical model was used and the result indicated that the reasons behind vaccine quality- and safety-related events were often complicated. The majority of the events could be classified as profit-driven events which meant that most of the events might be related to the motive of profit without oversight and effective regulations. Meanwhile, a minority of the events were identified as non-profit-driven events, which indicated that the challenges of vaccine safety would still exist even if a more effective regulatory system was in place. Enhancing supervision on vaccine production and putting plans in place for emergency preparedness can help mitigate the fall-out of future vaccine-safety related events.