Developments and changes in immunization programmes for human rabies vaccine

Introduction to the author:

Tang Qing is a researcher and doctoral supervisor of the Institute of Viral Disease Prevention and Control of the Chinese Center for Disease Control and Prevention. He has been engaged in research in the field of medical virology, and has undertaken the National Natural Science Foundation of China and the "863 Science and Technology" project, Sino-Japanese and Sino-French scientific and technological cooperation projects. as the person in charge of sub-projects, he has participated in major national scientific research projects such as agricultural public welfare industry scientific research projects and major national science and technology projects in the Eleventh five-year Plan, and has won a number of national, provincial and ministerial science and technological awards and special government subsidies.

Vaccines are a safe, effective and cost-effective public health intervention that protects susceptible populations from a number of pathogens and diseases. Typically such biologics are used primarily for prophylaxis, I .e., before exposure to a pathogen, and are ineffective after exposure has occurred. AndRabies is an exception. Because of the special pathogenesis of rabies and the relatively long incubation period, vaccination can play an important role in the intervention of rabies virus before or after exposure.

In the 19th century, Pasteur successfully vaccinated two patients with the earliest rabies neural tissue vaccine (NTV) made from raw animal ingredients, thus opening the post-exposure prophylaxis (PEP) against human rabies. The initial PEP immunization regimen included up to a dozen doses of vaccine over a period of 12 days or more.

Fermi and Semple et al. improved Pasteur's rabies vaccine by using phenol to partially or completely inactivate live virus in neural tissue to avoid iatrogenic infection. However, both vaccines require daily injections over a period of at least 14 days and a booster dose, with a minimum potency requirement of 0.3 IU/ml.

As a result of case reports of paralysis caused by myelin protein in rabies NTV or residual live virus in the vaccine, Fuenzalida and colleagues developed an improved neural tissue rabies vaccine, the suckling rat brain (SMB) vaccine, using newborn mice (thought to be free of myelin protein). The SMB vaccine is less immunogenic and still requires a 14-day daily injection regimen with booster doses given 10 and 20 days after completion of the primary immunization series. If the efficacy of the SMB vaccine can reach 1.3 IU/ml, a reduced dose regimen can be applied, I .e. daily injections for 7 days, with booster doses on days 10, 20 and 90 after the initial immunization, but the full 14-day immunization regimen is still required if anti-rabies serum is injected at the same time after exposure.

By the 1950 s and 1960 s, the application of new technologies made it possible to develop and develop a non-neurogenic rabies vaccine that could be more uniform and have less risk of adverse reactions. First, purified duck embryo vaccines (PDEVs) came out, and then in vitro cell culture was developed and perfected, allowing RABV to grow on human diploid and other cell lines. Advanced technology improves the purity, efficacy and uniformity of rabies vaccines, which can reduce the dose of human vaccines.

The study of the human diploid cell vaccine (HDCV) immunization program by Kuwert et al. of Essen, Germany, showed that the protective effect of 6 doses of Essen protocol was very significant, and all exposed vaccinees produced high levels of protective antibodies. The data on the immunogenicity, efficacy, and safety of HDCV in pre-exposure and post-exposure prophylactic injections were adopted by the WHO Expert Panel on Rabies and recommended the immunization program as a post-exposure vaccination regimen. Then, as new clinical evidence emerged, the sixth dose was canceled.

In 1984, WHO recommended a five-dose regimen for concentrated cell and tissue culture rabies vaccines with a minimum potency of at least 2.5 IU per dose, I .e. five doses of subvaccine (Essen regimen) on days 0, 3, 7, 14 and 30, with an optional booster dose on day 90. HDCV is the earliest modern cell and embryo culture rabies vaccine (CCEEVs), which is used as a control vaccine for subsequent vaccine development. It is required that the immunogenicity and safety of the subsequent vaccine should not be inferior to HDCV.

Today, concentrated and purified CCEEVs have become the vast majority of existing vaccines. The minimum potency of CCEEVs is 2.5 IU/intramuscular dose. According to the production matrix, CCEEVs can be divided into four types: human diploid cell vaccine (HDCV), purified chicken embryo cell vaccine (PCECV), primary hamster kidney cell vaccine (PHKCV) and purified Vero cell rabies vaccine (PVRV) developed in 1980 s. CCEEVs developed in recent years based on chicken embryo cells and Vero cells have comparable safety and efficacy to HDCV, but at a much lower cost.

In the WHO's later guidance documents, CCEEVs are the general designation of the recommended qualified human rabies vaccine. Efficacy, purity, potency and safety are the basic standards of modern vaccines. All CCEEVs included in the WHO recommendations have a comparable overall quality in terms of basic purity, potency and safety. CCEEVs have been widely used in the world for more than 30 years, which has greatly reduced the number of cases in areas with high incidence of rabies, which is sufficient to prove its safety and preventive efficacy. The large-scale production of Vero cell rabies vaccine ensures product consistency and inter-batch identity, and solves the problem of insufficient rabies vaccine production capacity to meet the needs of the global market. It is currently the most widely used rabies vaccine.

In the 1980 s, the Zagreb Institute of Public Health in the former Yugoslavia recommended a simplified post-exposure immunization procedure, I .e. 2 doses on day 0, 1 dose on day 7 and 21 respectively (Zagreb 2-1-1 scheme), and all vaccinees reached the protective antibody titer on day 14. The Zagreb regimen reduced the number of visits to three, with higher adherence and better early immunogenicity in vaccinators. In 1992, the Zagreb program became one of the WHO-recommended intramuscular immunization programs for rabies vaccine, and the Zagreb program was applied in many countries, including China.

In 2008, the Rabies Working Group of the Advisory Committee on Immunization Practice (ACIP), based on the data of rabies pathogenesis, animal experiments, clinical studies and epidemiological monitoring, proposed that 4 doses of vaccination combined with rabies immunoglobulin (RIG) can cause sufficient immune response, while the 5th dose of vaccine can not produce more favorable results, therefore, a 4-dose immunization regimen of intramuscular vaccine on days 0, 3, 7, and 14 is recommended, I .e., one less dose on day 28 of the Essen regimen. The 2013 WHO guidelines for post-exposure management of rabies added the 1 dose reduction Essen regimen as an alternative to rabies PEP. The 2018 WHO position paper identifies the 1-dose reduction Essen regimen and the Zagreb2-1-1 regimen as the primary recommended PEP regimen.

——Rabies vaccines and immunoglobulins: WHO position（2018）

Due to the insufficient production capacity and high price of CCEEVs in the world, PEP clinical trials of intradermal injection (ID) have been carried out in some regions. In 1991, the WHO Expert Committee on Rabies recommended intradermal administration of modern rabies vaccines for post-exposure prophylaxis. The first ID PEP regimen was administered within 90 days, but as clinical evidence accumulated,The ID regimen was gradually reduced to two 0.1 mL ID injections in the deltoid area of each arm over a 28-30 day period. Over time, a number of ID PEP protocols have been developed and proven to be very effective and widely used in countries where rabies is endemic in Asia. Some countries have introduced rabies vaccine ID programs for pre-exposure prophylaxis (PrEP) immunization of travellers, and the high serum positive conversion rate after vaccination confirms the effectiveness of ID immunization.

Modern CCEEVs, produced in highly purified cell culture systems, are among the most immunogenic vaccines and have been used worldwide for decades with ample evidence of safety and efficacy. These highly purified cell culture rabies vaccines were identical in clinical efficacy, thus using the same PrEP and PEP protocols recommended by WHO. However, some research data suggest that the vaccination regimen for PrEP and PEP can be further shortened and the required dose can be reduced. The ID PrEP scheme can be shortened to two visits in one week, I .e. two doses of 0.1 mL CCEEVs are inoculated with ID on days 0 and 7, and its immunogenicity and safety are not lower than those of the standard three-visit vaccination scheme (0.1 mL CCEEVs are inoculated with ID on days 0, 7 and 28 respectively).

Based on the IM PrEP study at a single visit and expert knowledge, indirect evidence was used to evaluate the IM PrEP protocol at 2 visits. Studies from Thailand, the Netherlands, and Belgium have shown that with a single vaccination with PEP, 99.5 to 100 percent of subjects can produce rabies virus neutralizing antibody (RVNA) titers higher than 0.5 IU/mL, and can generate sufficient memory antibody response to PEP after 1 year.

The relationship between vaccination dose (PrEP or PEP) and duration of circulating RVNA has been observed in several studies. RVNA titers were still detectable 9 years after initial vaccination in 80% of vaccine recipients in one of the studies. No significant differences in RVNA were observed in relation to vaccination dose or length of time after primary vaccination. Based on these data, in 2018 WHO proposed an updated reduced vaccination plan based on the original rabies vaccination plan to reduce the cost of PrEP and PEP, the number of vaccines and the number of outpatient visits.

PEP protocol (first exposure):

ID 2 point method: days 0, 3 and 7

Simplified 4-needle method: one dose on days 0, 3 and 7 and one dose on any day from 14 to 28

"2-1-1" procedure: one dose on the left and right upper arms on day 0 and one dose on days 7 and 21

PrEP Program:

ID 2 point method: one dose on day 0 and one dose on day 7

IM: One dose on days 0 and 7

——Rabies vaccines: WHO position paper – April 2018

At every stage of the development of new and improved human rabies vaccines and their vaccination regimens, the rabies immunization application has been using a multiple-shot approach, continuing to this day. Without increasing the risk of disease, reducing the number or frequency of injections will not only reduce direct costs (reducing vaccine doses and consumables used), but will also reduce the number of visits required, thereby reducing indirect costs (multiple trips, lodging and loss of income). Currently, the challenge is to embrace and implement these changes to improve access to life-saving PrEP and PEP and reduce the burden of preventive treatment for this deadly disease.

Main references:

1. WHO expert committee on rabies. World Health Organ Tech Rep Ser. 1984,709. 
2. Kuwert EK, Marcus I, Werner J, et al. Some experiences with human diploid cell strain-(HDCS) rabies vaccine in pre- and post-exposure vaccinated humans. Dev Biol Stand, 1978, 40:79-88. 
3. Kuwert EK, Marcus I, Höher PG, et al. Immunogenicity, efficacy and reactogenicity of a human diploid cell strain (HDCS) rabies vaccine in man; recommendations for pre- and post-exposure application (vaccination scheme). Med Klin, 1977, 72(18):797-805.
4. Vodopija I, Sureau P, Smerdel S, et al. Interaction of rabies vaccine with human rabies immunoglobulin and reliability of a 2-1-1 schedule application for postexposure treatment. Vaccine, 1988, 6(3):283-6.
5. Ren J, Yao L, Sun J, et al. Zagreb regimen, an abbreviated intramuscular schedule for rabies vaccination. Clin Vaccine Immunol, 2015, 22(1):1-5. 
6. Rupprecht CE, Briggs D, Brown CM, et al. (CDC) Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices. MMWR Recomm Rep, 2010, 59(RR-2):1-9.
7. WHO Expert Consultation on Rabies. Second report. World Health Organ Tech Rep Ser. 2013, 982.
8. Gongal G, Sampath G. Introduction of intradermal rabies vaccination - A paradigm shift in improving post-exposure prophylaxis in Asia. Vaccine, 2019, 37(Suppl 1):A94-A98.
9. Kong LY, Vincelette J, Laplante G, et al. Intradermal pre-exposure rabies vaccination in a Canadian travel clinic: 6-year retrospective observational study. CMAJ Open, 2018, 6(2):E168-E175.
10. O'Brien KL, Nolan T; SAGE WG on Rabies. The WHO position on rabies immunization - 2018 updates. Vaccine, 2019, 37(Suppl 1):A85-A87.
11. Jonker EFF, Visser LG. Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study. J Travel Med, 2017, 24(5):1-8.