cases were identified through the hospital - based active surveillance system of the hfrs maintained by the korean army . cases occurring from january 1 , 2002 , to january 1 , 2004 , were enrolled prospectively . for early detection of hfrs , patients with hfrs may have sudden onset of fever ; experience pain in the head , abdomen , and lower back ; and report bloodshot eyes and blurry vision . the patient 's face , chest , abdomen , and back often appear flushed and red , as if sunburned . a confirmed case of hfrs is defined as a positive result on the high - density particle agglutination test . for each case , one control was selected from among the other patients at each hospital where the case - patient had been hospitalized . the control was matched with the case - patient according to unit , age at the time of hospitalization ( 3 years ) , date of hospitalization ( 3 months ) , and date of transfer to the present unit ( 3 months ) . if no suitable control could be found , the intervals around the case - patient 's unit , age , date of hospitalization and date of transference were progressively widened until one or more potential controls were found . for each case - patient , all eligible controls were listed , and one suitably matched control was identified at random . as with the case - patients , the final decisions about each control patient 's eligibility for the study were made on the basis of a detailed review of hospital records . decisions about the eligibility of potential controls were made without knowledge of their vaccination status . vaccine had to be received at least 3 weeks before hospitalization because of the time required for antibodies to develop and because the incubation period is 3 weeks on average ( 5 ) . estimates of the relative odds of hfrs associated with vaccination were estimated by using methods developed by mantel and haenszel ( 6 ) , which are appropriate for matched designs . the protective effectiveness of the vaccine was estimated as 1 minus the relative odds associated with vaccine use , times 100 . ninety - five percent confidence limits for the effectiveness were derived from the 95% confidence interval ( ci ) of the relative odds . chicago , il ) . from january 1 , 2002 , to january 1 , 2004 , a total of 57 hfrs cases were identified among troops of the korean army . of one of three deaths occurred in previously healthy , vaccinated ( first and second doses ) personnel . twelve , 9 , and 2 cases occurred in personnel who were vaccinated with one , two , and three doses , respectively . most cases occurred in october ( 15.7% ) , november ( 35.7% ) , and december ( 17.1% ) , although disease also occurred during the spring and the summer ( figure 2 ) . hemorrhagic fever with renal syndrome cases among republic of korea military personnel , by month of onset , january 2002 to january 2004 . of the 54 persons identified with hfrs from january 2002 to january 2004 , those who were vaccinated within 3 weeks of hospitalization were excluded from analysis . because the effectiveness was calculated by comparing each dose ( exactly one to three ) with no vaccination , case - patients or controls not applicable to that comparison were excluded from each matched set . finally , 41 , 38 , and 31 matched sets were formed for one , two , and three doses of the hantavirus vaccine , respectively ( table ) . estimates of vaccine effectiveness according to the number of doses received rose from 25% ( 95% ci 78% to 68% ) for one dose to 46% ( 95% ci 35% to 78% ) for two doses to 75 % ( 95% ci 18% to 95% ) for three doses . when recipients for whom 1 year had passed since their second dose were excluded , effectiveness of two doses increased markedly to 70% ( 95% ci 9% to 92% ) . the protective effectiveness of the vaccine strongly depends on the number of doses . in particular , effectiveness increased when persons for whom > 1 year had passed since their second dose were excluded , which suggests that the protective effect of the second primary vaccination does not persist beyond the period recommended for having the booster dose . in addition , we do not know whether the recommended immunization schedule was optimal for military personnel and farmers , groups for whom hantavirus vaccination is recommended . the vaccination schedule should be epidemiologically relevant , immunologically effective , operationally feasible , and socially acceptable ( 7 ) . in a field study from the former republic of yugoslavia conducted by korean researchers , including the developers of the hantavirus vaccine ( 8) , no case of hfrs was observed among 1,900 vaccinees , while 20 confirmed cases were observed among 2,000 nonvaccinated controls . considering that our study showed low protective effectiveness for one or two doses , that no case of hfrs occurred in yugoslavian vaccinees before they received the full three doses was surprising . because the case - control studies were not experimental , they may be subject to biases . the most important potential biases that might affect this kind of study are detection and selection bias . if all cases of hfrs were identified , no detection bias would occur . because patients were identified prospectively by active surveillance , we believe that virtually all cases of hfrs diagnosed during the study period were identified . selection bias may occur when controls do not represent the general population . in this study , controls were selected randomly from a list of potentially eligible controls by using a systemic algorithm . confounding influences affect the results of a case - control study if controls differ from case - patients in characteristics related to risk of contracting the disease and likelihood of receiving the vaccine . since the population of this study consisted of military personnel , bias due to sociodemographic differences may be negligible . therefore , other candidate confounding factors determined by considering the military milieu were used as matching variables . therefore , while point estimates show effectiveness , this finding could be due to chance . of course , the range of point estimates in studies with relatively small samples can be wide , and wide confidence intervals that include zero are not uncommon in many studies on vaccine effectiveness ( 9 ) . however , caution is appropriate in interpreting our estimates of vaccine effectiveness . finally , this study represents a short - term ( 7.3 months average ) evaluation of protective effectiveness of three doses of the hantavirus vaccine . to assess the long - term effectiveness , protection
a case - control study in the republic of korea evaluated the protective effectiveness of the hantavirus vaccine . 
 point estimates showed increasing effectiveness with increasing numbers of doses received : 25% for one dose , 46% for two doses , and 75% for three doses . 
 all 95% confidence intervals overlapped zero ; therefore , the findings could be due to chance .