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Malaysian Society of Infectious Diseases & Chemotherapy

Guidelines for Adult Immunisation

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Message from Editor

Editorial Panel

Quick Guide

Contraindications and Special Considerations

Temporary Deferral of Immunisation

Route and Site of Administration

Post Vaccination

Anaphylaxis

Storage and Disposal of Vaccines

Vaccine Combinations

Multiple Vaccinations

Adverse Event Following Immunisation (AEFI)

Cholera

Diphtheria

Tetanus

Pertussis

Haemophilus influenzae

Hepatitis A

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Human Papillomavirus (HPV)

Influenza

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Measles

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Meningococcal Disease

Pneumococcal Disease

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Passive Immunisation

Avian Influenza

Chikungunya

Clostridioides difficile

COVID-19

Dengue

Ebola

Enterovirus 71

Human Immunodeficiency Virus (HIV)

Malaria

Zika

Adults Who Missed Childhood Immunisation

Elderly and Patients With Chronic Ilnesses

Healthcare workers

Human Immunodeficiency Virus (HIV)

Immunocompromised Patients

Miscellaneous Groups

Travelers

Vets & Animal Handlers

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Upcoming Vaccines​

Enterovirus 71 (EV71)

In this chapter:

Introduction

Enterovirus 71 (EV71) is a member of the Enterovirus genus of the Picornaviridae family. It is the second most common causative pathogens of hand-footand-mouth disease (HFMD), after coxsackievirus A16 (CVA16), and the most common aetiological agent isolated from HFMD patients complicated with neurological disorders. EV71 is an increasingly important neurotropic enterovirus in the post-polio eradication era. Although most HFMD do not result in serious complications, outbreaks of HFMD caused by EV71 can present with a high rate of neurological complications, including aseptic meningitis, encephalitis, acute flaccid paralysis, pulmonary complications, cardiovascular complications and fatal consequences.

HFMD is a major emerging infectious disease in Asia-Pacific region, with increasing incidence over the past 2 decades and of public health importance. Epidemics occur in countries including China, Taiwan, Singapore, Japan and Malaysia. Across South East Asia, HFMD affects approximately 2,000,000 children every year.

In Malaysia, since the initial enterovirus 71 (EV71) outbreak in Sarawak in 1997, data showed that EV71 outbreaks occur in a regular cyclical pattern every 3 years. In the 2006 outbreak, there were 14,000 cases with 13 deaths. All outbreaks documented (1997, 2000, 2003, and 2006) have been predominantly caused by EV71 of genogroup B. Outbreaks of HFMD were also reported in Peninsular Malaysia, where EV71 and CVA16 were the main aetiological viruses isolated and more than one sub-genogroup of EV71 co-circulate in the past outbreaks in the country. In 2018, HFMD soared to near epidemic levels with over 55,000 cases, with the outbreak in Penang involving more than 3,700 cases.

EV71 virus is divided into 3 genotypes on the basis of VP1 sequence: A, B, and C, then into 11 sub-genotypes. Some viral sub-genotypes seem to have great potential for epidemics, whereas others have more-indolent, lowlevel circulation. C4 is the most prevalent EV71 genotype found in China, Hong Kong, Korea, and Vietnam, whereas B5 is the most common genotype circulating in Japan, Malaysia, and Taiwan.

The virus is transmitted through direct contact with nasopharyngeal secretions, saliva, fluid from blisters, or stool of infected persons. Indirect transmission occurs through contaminated materials touched by an infected person. Patients are infectious during the stage when they have high fever. Several antiviral strategies are under investigation, including small molecules and antibodies.

Vaccines

 

Several reviews on EV71 vaccine development have been published. Since morbidity and mortality from EV71 infection is low, the major effect of this vaccine will be to reduce hospital admissions. EV71 vaccines being developed and at various stages of clinical trials include:

  1. Inactivated whole-virus
  2. Live attenuated virus
  3. Virus-like particles
  4. DNA vaccines and recombinant vector vaccines
  5. Recombinant proteins and synthetic peptides

Five organisations have completed pre-clinical studies focused on the development of inactivated EV71 whole-virus vaccines, including vaccine strain screening, process optimisation, safety and immunogenicity evaluation, and are in different stages of clinical trials. Three of these are companies in mainland China (Institute of Medical Biology, Chinese Academy of Medical Science (CAMS), Sinovac Biotech Co. Ltd. and Beijing Vigoo Biological Co.Ltd.), that have successfully completed phase III randomised, double-blinded, placebo controlled trials. These Phase III clinical trials have involved more than 30,000 infants and children. All three vaccines are inactivated whole-virus alum-adjuvant vaccines that use C4 genotype virus strain. 

China Food and Drug Administration (CFDA) has approved the three EV71 vaccines against HFMD in children. The first vaccine approval was in 2015 for CAMS vaccine candidate, followed by the second vaccine made by Sinovac Biotech in 2016. 

Two other formalin-inactivated whole-virus vaccines, developed by the National Health Research Institutes (NHRI) of Taiwan and Inviragen of Singapore, have also completed Phase I clinical trials. The results of clinical trials suggest a promising future for the clinical use of EV71 vaccines. 

Monitoring for epidemiological variations in EV71 will be necessary to determine whether the vaccine has ongoing, long-term efficacy and detection of any genogroup replacement. The next step would be development of bivalent or multivalent vaccines, to protect against other common HFMD pathogens including CVA16.

Vaccines Available in Malaysia

 

Currently no vaccine is registered.

Mode of Administration

 

Intramuscular administration and various dosage regimens are being assessed in clinical trials.

Target Group in Malaysia

 

When available, the probable target population for vaccination would be young children especially those under 3 years, who are the most susceptible to severe disease.

Evidence for Effectiveness

 

A multicentre randomised controlled trial done in China demonstrated vaccine protection against EV71. This trial included more than 10,000 children (aged 6–35 months), showed vaccine efficacy of 90.0% for EV71-associated HFMD and 80.4% for EV71-associated disease (including herpangina, neurological complications, and non-specific illnesses caused by EV71). Safety profile was satisfactory and the results are similar to those for inactivated poliovirus vaccine.

References

  1. Chua, K. B., & Kasri, A. R. (2011). Hand foot and mouth disease due to enterovirus 71 in Malaysia. Virologica Sinica, 26(4), 221–228. https://doi.org/10.1007/s12250-011-3195-8
  2. Crawford, N. W., & Graham, S. M. (2013). EV71 vaccine: protection from a previously neglected disease. Lancet (London, England), 381(9882), 1968–1970. https://doi.org/10.1016/S0140-6736(13)61124-1
  3. Kuo, R. L., & Shih, S. R. (2013). Strategies to develop antivirals against enterovirus 71. Virology journal, 10, 28. https://doi.org/10.1186/1743-422X-10-28
  4. Li, R., Liu, L., Mo, Z., Wang, X., Xia, J., Liang, Z., Zhang, Y., Li, Y., Mao, Q., Wang, J., Jiang, L.,Dong, C., Che, Y., Huang, T., Jiang, Z., Xie, Z., Wang, L., Liao, Y., Liang, Y., Nong, Y., … Li, Q.(2014). An inactivated enterovirus 71 vaccine in healthy children. The New England journal of medicine, 370(9), 829–837. https://doi.org/10.1056/NEJMoa1303224
  5. Li, Y.P., Liang, Z.L., Xia, J.L., Wu, J.Y., Wang, L., Song, L.F., Mao, Q.Y., et al. (2013). Immunogenicity, Safety, and Immune persistence of A Novel Inactivated Human Enterovirus 71 (EV71) Vaccine: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial, The Journal of Infectious Diseases, Volume 209, 46–55, https://doi.org/10.1093/infdis/jit429
  6. Liang, Z. L., Mao, Q. Y., Wang, Y. P., Zhu, F. C., Li, J. X., Yao, X., Gao, F., Wu, X., Xu, M., & Wang, J. Z. (2013). Progress on the research and development of inactivated EV71 whole-virus vaccines. Human vaccines & immunotherapeutics, 9(8), 1701–1705. https://doi.org/10.4161/ hv.24949
  7. Liang, Z., Mao, Q., Gao, F., & Wang, J. (2013). Progress on the research and development of human enterovirus 71 (EV71) vaccines. Frontiers of medicine, 7(1), 111–121. https://doi. org/10.1007/s11684-012-0237-z
  8. Ooi, M. H., Wong, S. C., Lewthwaite, P., Cardosa, M. J., & Solomon, T. (2010). Clinical features, diagnosis, and management of enterovirus 71. The Lancet. Neurology, 9(11), 1097–1105. https://doi.org/10.1016/S1474-4422(10)70209-X 
  9. Podin, Y., Gias, E. L., Ong, F., Leong, Y. W., Yee, S. F., Yusof, M. A., Perera, D., Teo, B., Wee, T. Y., Yao, S. C., Yao, S. K., Kiyu, A., Arif, M. T., & Cardosa, M. J. (2006). Sentinel surveillance for human enterovirus 71 in Sarawak, Malaysia: lessons from the first 7 years. BMC public health, 6, 180. https://doi.org/10.1186/1471-2458-6-180
  10. Reed, Z., & Cardosa, M. J. (2016). Status of research and development of vaccines forenterovirus 71. Vaccine, 34(26), 2967–2970. https://doi.org/10.1016/j.vaccine.2016.02.077
  11. Solomon, T., Lewthwaite, P., Perera, D., Cardosa, M. J., McMinn, P., & Ooi, M. H. (2010). Virology,epidemiology, pathogenesis, and control of enterovirus 71. The Lancet. Infectious diseases, 10(11), 778–790. https://doi.org/10.1016/S1473-3099(10)70194-8
  12. Xu, J., Qian, Y., Wang, S., Serrano, J. M., Li, W., Huang, Z., & Lu, S. (2010). EV71: an emerging infectious disease vaccine target in the Far East?. Vaccine, 28(20), 3516–3521. https://doi. org/10.1016/j.vaccine.2010.03.003
  13. Zhang, D., Lu, J., & Lu, J. (2010). Enterovirus 71 vaccine: close but still far. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 14(9), e739–e743. https://doi.org/10.1016/j.ijid.2009.12.002
  14. Zhu, F. C., Meng, F. Y., Li, J. X., Li, X. L., Mao, Q. Y., Tao, H., Zhang, Y. T., Yao, X., Chu, K., Chen, Q. H., Hu, Y. M., Wu, X., Liu, P., Zhu, L. Y., Gao, F., Jin, H., Chen, Y. J., Dong, Y. Y., Liang, Y. C., Shi, N. M., … Shen, X. L. (2013). Efficacy, safety, and immunology of an inactivated alumadjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet (London, England), 381(9882), 2024–2032. https://doi.org/10.1016/S0140-6736(13)61049-1