Vaccine

Volume 17, Issues 20–21, 4 June 1999, Pages 2569-2575
Vaccine

Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax®)

https://doi.org/10.1016/S0264-410X(99)00057-2Get rights and content

Abstract

Hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) and result in severe human morbidity and mortality. Safe and effective vaccines are needed urgently in order to reduce the incidence of human illness. Hitherto studies of hantavirus vaccine efficiency have been limited to individuals at low risk of infection. In this study the immune response to an inactivated hantavirus vaccine was measured in 64 human volunteers at high risk of infection by virtue of residence and occupation. 30 d after vaccination, 79% of subjects developed a significant hantavirus antibody titre as measured by immunofluorescence (IFA) and 62% by enzyme linked immunosorbent assay (ELISA). Seroconversion rates increased to 97% one month after the booster dose. Neutralising antibody titres paralleled this trend with 13% of vaccine recipients producing neutralising antibody one month after the first dose and 75% of vaccine recipients responding one month after boosting. Antibody titres had declined by one year, however, with only 37% and 43% of sera positive by IFA and ELISA, respectively. Re-vaccination at this time produced a vigorous anamnestic response with 94% and 100% of vaccine recipients yielding positive antibody titres. Only 50% of the sampled population, however, produced neutralising antibodies following the booster dose one year later. The vaccine was well tolerated and there were no apparent differences in the responses of males and females. However, further improvement of this vaccine is necessary in order to induce a more longlasting humoral immune response.

Introduction

The clinical syndrome now known as haemorrhagic fever with renal syndrome (HFRS) has been recognised in the medical literature of Europe and Asia under a variety of names. Epidemic haemorrhagic fever first attracted widespread attention during the Korean conflict (1950–1953). The disease ranges from mild to severe, depending upon the subtype of the infecting agent. Hantaviruses that group serologically with the prototype Hantaan virus generally cause a severe disease, with a distribution throughout Asia extending into the former Soviet Union, the Transcaucus and into eastern Europe [1].
Approximately 200,000 cases of HFRS occur annually worldwide. Since 1951, between 500 and 2,000 patients with HFRS have been hospitalized annually in Korea as a consequence of infection with either the Hantaan or Seoul virus strains which are prevalent in this region. Until recently, neither prophylactic measures nor chemotherapeutic agents were available for the prevention or treatment of HFRS. This illness is still considered one of the most important public health problems in the Republic of Korea, as well as in other areas of Eurasia. In 1984, the World Health Organization recommended developing an effective, inactivated vaccine against HFRS as soon as possible. The Working Group for Haemorrhagic Fevers with Renal Syndrome described the development of an inactivated vaccine against Hantaan virus, prepared in the brains of newborn mice. Vaccine immunogenicity and efficacy were evaluated based on challenge experiments with immunized mice. The anticipation was that such protective immunity would be observed in humans administered with this vaccine.
In addition to Hantaan, Seoul and Puumala viruses also cause HFRS. In contrast, the more recently described Sin Nombre virus causes an hantavirus pulmonary syndrome (HPS). Hantaan virus causes severe symptoms with a mortality of 5–10%, whereas HPS infection can result in mortality rates in excess of 60% [2], [3], [4], [5], [6], [7]. Clearly, there is an urgent need to develop effective vaccines against these viruses. In 1984, the World Health Organisation (WHO) recommended the development of an effective inactivated vaccine against HFRS as soon as possible. As a result, Lee and An [7], [8], [9] developed an inactivated vaccine against Hantaan virus infection. This Hantaan virus vaccine is prepared from the Hantaan virus strain ROK 84–105 grown in suckling mice brain and has been shown to induce protective immunity in mice and humans. It is currently produced commercially under the name Hantavax® and is licensed for use in the Republic of Korea. However, there has not been any detailed investigation of immune responses in vaccinated individuals at high risk of infection by virtue of their occupation and/or their residing in an area where the prevalence of rodent infection is high. Thus the overall protective value of the Hantaan virus vaccine cannot be stated with certainty.
The aim of this study was to assess the antibody responses to the inactivated virus vaccine Hantavax® in 64 human volunteers using a schedule of three doses delivered over a period of one year. The induction of anti-hantavirus antibodies has been measured with a view to optimising antibody levels after the third, booster dose. In addition, the safety and efficacy of this vaccine has been evaluated.

Access through your organization

Check access to the full text by signing in through your organization.

Access through your organization

Section snippets

Formalin-inactivated Hantavax® vaccine

The inactivated vaccine has been prepared from the Hantaan virus strain ROK 84–105 grown in suckling mouse brain. ROK 84–105 was isolated directly from the blood of an HFRS patient in Vero-E6 cell cultures [10], [11]. This isolate was passaged three times in the brains of suckling ICR mice and seven times in the brain of suckling SD rats respectively and then used as a seed virus for vaccine preparation. Virus was purified from infected suckling mouse brain by protamine–sulphate precipitation

Characterization of antibody responses

None of the vaccine recipients were positive for anti-Hantaan antibodies virus prior to immunisation. The seroconversion rates among the vaccinated volunteers are shown in Fig. 1. Thirty days after immunisation 51 of 64 individuals (79.7%) were positive by IFA (titre 1:32 by serial dilution); 40 of these sera were considered positive also by ELISA (62%). The ELISA titres yielded a greater geometric mean titre (GMT) compared with IFA (1:120 as opposed to 1:32), possibly reflecting either the

Discussion

Immunisation of volunteers with a novel hantavirus vaccine (Hantavax®) resulted in 97% seroconversion by the IFA test and 75% by the plaque reduction neutralisation antibody test (PRNT) following two intramuscular doses of vaccine one month apart. One year after the initial vaccination, however, these antibody titres had dropped significantly to 37.5% and 21.4% respectively. A single dose 12 months after initial vaccination boosted the seropositivity rate to 93.8% as determined by IFA, 100% by

Acknowledgments

The authors want to thank Professor H.W. Lee for his valuable information and judicious prodding and the members of the Division of Arbovirology, National Institute of Health, Korea who assisted and supported this work in many ways include Dr. H.K. Shin, Dr. Y.J. Jeong, Mr. J.W. Nam and Ms. S.Z. Ban.

References (23)

  • World Health Organisation. Working group on viral haemorrhagic fever and viral neurological diseases. World Health...

    • Cited by (74)

    • Hantavirus infections

      2019, Clinical Microbiology and Infection
      Citation Excerpt :

      In Asia, the Republic of Korea, Hantavax® has been used for a number of years. The vaccine is derived from formalin-inactivated HTNV-infected suckling mouse brain, but frequent booster doses are needed for protective immunity [171]. In China, several different formalin-inactivated vaccines from animal tissues have been produced and used, but none has been approved for use in European countries (reviewed in ref. [172]).

    • Hantavirus infections and their prevention

      2001, Microbes and Infection

    • Hantavirus infections in Europe and their impact on public health

      2013, Reviews in Medical Virology

    • Hantaviruses: Molecular biology, evolution and pathogenesis

      2005, Current Molecular Medicine

    • Hantavirus infection

      2005, Journal of the American Society of Nephrology

    • Hantaviruses: Immunology, treatment, and prevention

      2004, Viral Immunology
    View all citing articles on Scopus
    View full text
    Copyright © 1999 Published by Elsevier Ltd.