Chickenpox is a common, multiple, and highly contagious childhood disease characterized by a systemic vesicular eruption and mild signs. Pathogen – Varicella-zoster virus (Varicella-zoster Virus, VZV) belongs to the family Herpesviridae, subfamily Alphaherpesvirus, is a double-stranded DNA virus with only one serotype. The diameter of the viral nucleocapsid is about 80nm-120nm, in the shape of an icosahedron, surrounded by an inner membrane and an envelope partly derived from the cell membrane.
Takao Ozaki and Yoshizo Asano, two pediatric experts from Aichi Prefecture, Japan, published a review in Vaccine, let us listen to the “country of origin” of chickenpox vaccine – the past and present of chickenpox vaccine told by Japanese scholars.
In the 1950s, thanks to the ever-changing field of virology, Japan was experiencing a wave of vaccine development. Vaccines for measles, mumps, rubella, and polio were successfully developed one after another. In 1959, Takahashi Liming served as an assistant professor in the Department of Microbial Diseases, Osaka University. Professor Yoshiomi Okuno, the head of the department at that time, was the person in charge of developing vaccines for measles, mumps, and rubella. However, the chickenpox vaccine is hard! Because VZV is unstable at high temperature and has strong cell affinity, it becomes latent after the initial infection, making it difficult to obtain cell-free virus.
Professor Takahashi’s initial choice was to study measles and polio. It was not until 1964 that something happened that affected his research direction. At that time, Takahashi Liming was studying in the United States again. His 3-year-old son had chickenpox and had severe symptoms, with blisters all over his body and a high fever. Professor Takahashi and his wife guarded him day and night and combined with comprehensive treatment, the child’s condition gradually improved. Subsequently, Professor Takahashi began to pay attention to the work of live attenuated chickenpox vaccine. In 1970, he officially started his varicella vaccine research career.
In 1971, a child with the surname Oka may not have known that the typical chickenpox that occurred on him would avert or alleviate the suffering of children all over the world in the future. A virus strain isolated by Professor Takahashi from the vesicle fluid of his body was first subcultured in human embryonic lung cells (34°C) for 11 times in human embryonic lung cells, and then in guinea pig embryonic cells for 12 times using a classic attenuation protocol. Subculture (37°C), and then subculture three times in WI-38 cells, and two times in MRC-5 cells, and obtained the main seed batch of VZV vaccine Oka strain. This was followed by 2-3 passages in MRC-5 cells to prepare working seed batches for vaccine production.
After a series of safety and efficacy tests, in 1974, the varicella vaccine showed its power for the first time. At that time, a patient in the pediatric ward of a hospital developed chickenpox. The researchers immediately vaccinated 23 other uninfected children with live attenuated chickenpox vaccine, and the result was 100% protection. The researchers published an article in The Lancet to further elaborate on its safety and effectiveness. The vaccine was then used in children with leukemia, because chickenpox, which may be “soft” to us, may have serious consequences for them.
Different from the clinical research of other vaccines, the early clinical research of varicella vaccine mainly focuses on high-risk groups that may develop severe varicella symptoms, such as acute leukemia, tumors, nephrotic syndrome, etc., while other vaccines generally select healthy groups. Therefore, from the results of good clinical trials, it is also assured that the vaccine can be applied to these populations. In 1984, eight European countries approved the vaccine for use in high-risk groups. In 1985, WHO also recognized and recommended Oka strain as the production strain of varicella vaccine. From 1986 to 1987, Japan approved the varicella vaccine for children over 1 year old, one injection, voluntary vaccination. In 1995, the United States also approved the attenuated vaccine, and it was included in the routine immunization program the following year.
Riaki Takahashi’s research is finally recognized! In 2011, the Financial Times reported “First Person: “I created the vaccine for chickenpox””. At this point, 32 million doses of the varicella vaccine had been administered in more than 80 countries. In December 2013, Professor Riaki Takahashi passed away at the age of 86. The New York Times issued a special eulogy, praising his great contribution in his life!
Although the vaccine is widely considered to be safe, there have been some objections since the research phase, mainly around whether this attenuated live vaccine will cause vesicles and potential tumorigenic risks. Although such a problem has not yet occurred, at least, there is no exact correlation research data, but after the 1990s, allergic reactions gradually appeared. At that time, the vaccine used gelatin as a stabilizer. Kumagai et al confirmed that allergic reactions were related to gelatin. In 2000, the gelatin-free varicella vaccine was approved for use in Japan. Compared with before, the immune response produced by the vaccine remained unchanged, but the incidence of adverse reactions should indeed decrease.
In terms of vaccine effectiveness, it was previously reported that the positive conversion rate can reach 86.1% to 90%. Then it was recently reported that the positive conversion rate was 75.1% using hemagglutination test, which is lower than the previously reported data. However, Japan has always focused on measuring the level of antibodies, that is, the response level of humoral immunity. In future research, it may be possible to consider the level of cellular immunity, such as IFN-γ levels or skin tests.
Breakthrough varicella, defined as cases of varicella occurring more than 42 days after immunization, may be a current data point that could call into question the efficacy of the vaccine. In fact, it was discovered in the early stage that even if the antibody level increased, breakthrough chickenpox still inevitably occurred. The incidence of breakthrough varicella after a single dose of immunization in Japan fluctuates greatly, and the reported data range from 2.1% to 34.2%. After one shot of routine immunization in the United States, the early protection effect is ideal. But 8 years later, breakthrough chickenpox outnumbered even natural chickenpox patients. The United States has updated its immunization strategy. After two doses of vaccination, the number of chickenpox patients in 2013 was reduced by 80.6% compared with 2006.
To increase coverage and reduce breakthrough varicella, Japan introduced varicella into routine vaccination in October 2014. At the same time, the two-needling method has also been put on the agenda. At present, it is recommended that the immunization interval be greater than 3 months before the age of 3, and more data support is needed for the optimization strategy. In the future, some Japanese scholars also suggested expanding the scope of monitoring population, not limited to the monitoring of chickenpox epidemic in young children. In addition, the measles, mumps, varicella vaccine has been approved for use in countries such as Europe and the United States, and Japan is also actively following up. The relationship between chickenpox vaccine and shingles also needs more research to confirm whether it is caused by the vaccine strain or the wild strain. Through these means, it is expected to increase and maintain a certain coverage of varicella vaccination and strengthen the control of varicella outbreaks.
In my country, people generally think that chickenpox is a self-limiting childhood disease with little harm. In addition, there was no specific vaccine for prevention in the past, so although it was widely prevalent, it rarely attracted attention from all parties. Chickenpox is not a legally notifiable infectious disease in my country. In 1998, the first survey of VZV serological prevalence in some urban residents in my country showed that the positive rate of VZV antibody was 68.76%. Since 2005, chickenpox has entered the China Disease Surveillance Information Reporting Management System, and since 2007 it has been released in the China CDC Public Health Data Information System. From 2007 to 2013, the highest incidence rate was 30.04/100,000 in 2011, and the lowest was 20.45/100,000 in 2007. Chickenpox occurs throughout the year, and winter and spring are the seasons of high incidence, with the highest incidence in December, accounting for about 43% of the annual incidence. The number of patients under the age of 7 accounted for 40.22% of the total number of patients. From 2007 to 2012, the top seven provinces according to the number of cases were Guangdong, Sichuan, Shandong, Hubei, Zhejiang, Beijing, and Shanghai, which were one of the main causes of public health emergencies. one.
According to the epidemic data, the incidence of chickenpox in my country is lower than that in other countries. It may be that the current surveillance report of chickenpox in my country is still incomplete, and the number of reported cases is far lower than the actual number of cases. Chickenpox has actually become one of the infectious diseases with the highest morbidity, and the social and economic burden it causes is heavy, which is no less than other epidemic infectious diseases that have been included in the national immunization program.