Pan American Health Organization PAHO/ACMR 14/19 Original: English
FOURTEENTH MEETING OF THE ADVISORY COMMITTEE ON MEDICAL RESEARCH
Washington, D.C. 7-10 July 1975
OBSERVATIONS ON THE SEROEPIDEMIOLOGY OF TYPHUS IN BOLIVIA
AND THE STATUS OF THE ATTENUATED VACCINE FIELD TRIALS
The issue of this document does not constitute formal publication, It should not be reviewed, abstracted, or quoted without the consent of the: Pan American Health Organization. The authors alone are responsible for statements expressed in signed papers. STATUS OF THE TYPHUS VACCIJE5 PROJECT írT BOLIVIA - 1975
Prepared by: Charles L. Wisseman, Jr., M.D.
For: The Bolivia-PAHO-University of Maryland
Collaborating Group.
Background: Although louse-borne typhus has been recognized as a distinct disease entity in Bolivia for only about 50 years, it likely has existed there since the time of the Spanish conquistadors, and has established itself as a highly endemic disease. In recent years, the number of reported cases has declined substantially. There is reason to believe, however, that a large amount of unrecognized and inapparent typhus transmission is continuing, although on occasion a classical village outbreak occurs (e.g. Canton Incla, Nov. 1971 to
Feb. 1972). On the other hand, there are some suggestions that at least in some areas transmission may be declining due possibly to changing conditions and education. If true, this would be an important trend which deserves quantitation and analysis in relation to policy decisions about the need for extensive typhus control programs and the nature of the control program.
Present status of tvuhus and typhus vaccine studies in Bolivia. Beginning
in 1968, the Department of Microbiology of the University of Maryland M!edical
School, under the auspices of the Pan Anerican llealth Organization, has been work- ing in close collahoration with the Ministry of Health of Bolivia through the
Instituto Nacionale de Enferinedades Transmisibles to study typhus in the Bolivian highlands and to evaluate the living attenuated E strain vaccine as a potential means for the control of typhus.
a. Epidemiological considerations. The progran has provided the opportunity to perform limited epidemiological studies through the analysis of prevaccination serium specimens, recarding them as cross-sectional serosurveys of populations in several parts of the Bolivian altiplano. Age specific CF antibody incidence plots from most of the areas sampled yield a pattern typical -2-
of a high endemicity of typhus. On the assumptions that these antibody profiles were being maintained in a steady state and that they were representative of a
substantial portion of the typhus-endemic zone, then many thousands of typhus
infections (unrecognized) must be occurring annually to maintain this age-specific
antibody profile in a steady state.
It has not yet been possible to study the epidemiological situation in
detail. However, there are some suggestions, which appear of potential signifi-
cance to the author of this report, that at least in some areas the requisite
steady state is not being maintained. Hard data to support this are not available
and what follows is more inmpression than science, but it points up the need for
the acquisition of certain kinds of data before rational policy decisions about
typhus control can be formulated.
There is a large potential bias in these impressiohs. For practical reasons,
the area studied had to be accessible by road. These areas may be enjoying a
change in living conditions that is not representative of the vast areas which
are not located on main cormnunication lines. llowever, it seems significant that
casual examination of the people in the study areas did not reveal a heavy louse
population. Indeed, it was impossible to collect enough lice, as an incidental
activity, to perform insecticide resistance tests. Although no concerted effort
was made to quantitate lousiness, it was apparent that in the study areas lousiness
was a problem smaller by orders of magnitude as compared with epidemic and
endemo-epidemic areas in Africa. Undoubtedly, this varies from comnunity to
commnunity, but it would seem crucial to have quantitative data on the louse
burden of the population in different parts of the country as well as information
on the patterns of insecticide resistance in order tp assess properly the typhus
problem.
In addition to this, there is some suggestion for a reduction in typhus
transmission in certain areas in recent years. For example, in the first sampling in 1968, one village stood out because the local inhabitants claimed not to have had anytyphus cases in 20 years, a fact which was substantiated by the age-specific typhus antibody pattern revealed bvy our laboratory tests. In the most recent study, involving over 8,000 people on the southeastern coast of
Lake Titicaca, a relatively affluent area, only about 18% of the population had typhus CF antibodies and the age-specific antibody pattern suggested a relatively low level of typhus transmission in the last t-¿o decades.
Cross-sectional serosurveys repeated at intervals of 3-5 years, with adequate sampling of the 1-10 year age groups, in selected representative areas could help establish trends in typhus transmission economically without having to await the development of a sophisticated, costly national reporting system and diagnostic facility.
In view of the low number of reported cases of typhus and of classical village outbreaks in recent years, it is the author's opinion that quantitative data of the kind described should be obtained before an expensive large-scale vaccination program is undertaken. It may be that living conditions are changing sufficiently rapidly in many areas that typhus will disappear spontaneously without specific control measures. Health education in the schools is probably an important factor. Some areas, however, miqht be identified which would benefit from specific typhus control measures, such as vaccine, both on a cost-benefit and a humanitarian basis.
b. Typhus vaccine studies. On the assumption that specific typhus control' measures were indicated in Bolivia, a step-wise program was developed for the evaluation of the living attenuated E strain typhus vaccine as a possible means by which the objective of typhus control could be accomplished. There was evidence that a single dose of this vaccine would donfer long-lasting immunity -4-
to typhus fever. The ¢cpacity of the vaccine to prctect against disease was
éstablished in a controlled study during a large epidemic in central Africa
(conducted by the author of this report under aITO auspices). Reactions to the vaccine are well-recognized. They are not serious but they do affect the acceptability of the vaccine by the population. In the severe enidemic situation, even moderately severe reactions are preferable to the risk of death from unmodified disease. In the endemic situation, where many mild or inapparent infections occur and where the population is not terrorized by the visible effects of classical typhus, reactions of a moderate nature might be unacceptable. This is the situation in Bolivia. Hence, it was necessary to ascertain the reaction rate and acceptability of the E strain vaccine under the conditions that obtain in the Bolivian type of typhus endemicity.
Two studies have been carried out in Bolivia to date.
The first was carried out in 3 widely separated areas in 1970-71. The practical
considerations of this study peraitted reasonable quantitative measurements of the
changes in the typhus antibody profile of the vaccinated population. The results were as expected. A high conversion rate swas induced in each area and the resulting profile of the populations suggested that a high degree of immunity was induced
in all age groups in such a way that significant transmission would have been
unlikely. Quantitation of reactions was not precise. However, it was the
impression of health authorities that the vaccine was acceptable from their point
of view.
A second study was performed between November 1973 and January 1974. The
design of this study was somewhat different than the first. It was conducted in
a single area, easily accessible by road, on the snutheastern coast of Lake Titicaca. -5-
The population, over 8,000 total, was distributed along a coastal road over a
20-39 kmJ distance, with a series of village centers, although it was in fact relatively dispersed. It was engaged primarily in agricultural and fishing activities, easily accessible.
Bolivian health personnel assumied primary responsibility for executing this study, with the assistance of one PAHO vaccine organizer, the supervision of the author and observers from PMHO. The area was divided into 4 zones. Bolivian physicians were recruited to make daily observations of a sample of the population for reaction from 1-21 days post-vaccination.A total of 3737 (43.6%) of the total population was enrolled.
Serum specimens were obtained from a sample (21%) of the vaccinated population prior to vaccination and between 6 and 8 weeks after vaccination (10.5%). Sixteen percent of the population was sampled for reactions.
Half of the vaccinated population (1870) received 105'5 EID 5 0 of the E strain typhus vaccine and half (1867) received tetanus-diphtlieria toxoid, both given subcutaneously by Ped-O-Jet.
The results are sunmmarized in the accompanying tables.
Both typhus and tetanus-diphtheria vaccines induced some degree of both local and systemic reactions, with the typhus vaccine giving a somewhat higher rate. Only the typhus vaccine gave late reactions (9-21 days). Details are recorded in accompanying tables. No serious reactions were detected by this intensive surveillance with either vaccine. In the judgement of the Bolivian health officials, this degree of mild reaction was within the acceptable range.
Because of some practical and communication problems, it was not possible to segregate the post-vaccination serum specimens according to the type of vaccine received. If, however, one assumes that the post vaccination sample included equivalent numbers of E strain and tetanus-diphtheria toxoid recipients, the change in typhus antibody titers was comparable to that expected from previous experience. -6-
Sumraary and Conclusions.
1. It appears to be feasible, with relatively simple precautions, to administer the living attenuated E strain vaccine to rural populations in
"el campo" in Bolivia bh means of the Ped-O-Jet.
2. Some reactions, both early and late, occur in a relatively high proportion of vaccinees, as determined by intensive surveillance. They are mild to moderate in severity. The early reactions are of similar magnitude, though somewhat more frequent, than those of Tetanus-Diphtheria toxoid. The late reactions were relatively mild and less frequent. No severe or serious reactions were encountered. They were judged by Bolivian health authorities to be within the acceptable range.
3. The E strain vaccine in the dose employed induces a high proportion of antibody conversion which changes dramatically the antibody profile of the vaccinated population.
4. 1nthe basis of sero-epidemiology, it appears that a large amount of unrecognized tynhus transimission is occurring in the Bolivian highlands, as opposed to the small number of recognized and reported typhus fever.cases. The
age-specific incidence of antibodies, and the age distribution of cases in villaqe outbreaks, are consistent with a highly endemic form of typhus. Some observations, however, suggest that typhus transmission may be diminishing spontaneously, at
least in some areas. It is suggested that before a policy decision is made
regarding the advisability of a large scale typhus vaccination program, a systematic quantitative study be made to assess the true incidence, trends and need for
active mass control measures. BOLIVIA-2 (1973-7'): CHARACTERISTICS OF THE VACCINATED POPULATIOI'NS
AGEGROU AGE GROUP E STPAIN 1 TET-DIp2 TOTAL POP. (YRS) NO. .NO. % NO. % .
TOTAL 1870 21.8 18F7 n 21.8 8566 100
1 - 4 220 11.8 261 14.0 1071 12.5
5 - 9 281 15.0 311 16.7 1106 12.9
10 - 14 270 14.4 289 15.5 1068 12.5
15 - 19 236 12.6 200 10.7 1122 13.1
20 - 863 46.2 806 43.2 4199 49.0
1 LOT CRD - 3 E STRAIN TYPHUS VACCINE
A. NOMINAL DOSE 105'5 EID 50 B. MEASURED PFU 104.58 5 58 C. DERIVED DOSE 10 . EID 5 0
2 TETANIJS - DIPHTHERIA 1TOXOID. DOSE 0.5 ML BOLIVIA-2: (i1973-74): PRE-VACCINATION TYPHUS CF TESTS1
AGE NO. NEG. POS. DOUBTFUL AC GROUP (TOTAL) NO. % NO. % NO. % NO.
0-4 0 - -
5-9 0 - - . .
10 - 14 _ 161 119 73.91 10 6.21 15 9.32 17 10.56
15- 19 122 85 69.67 12 9.84 $ 8 6.56 17 13.93
20 - 29 155 79 50.97 25 16.13 22 14.19 29 18.71
30- 39 122 63 51.64 18 14.75 29 23.77 12 9.84
40 - 49 101 29 28.71 34 33.66 24 23.76 14 13.86
50 -59 79 14 17.72 28 35.44 26 32.91 11 13.92
60- 69 21 30.4i3 23 33.33 12 17.39 11 15.94
TOTAL 8092 410 50.68 150 18.54 136 16.81 113 13.97
1 COMPLEMENT FIYX4TION TESTS BY MICROTITER IfqETHOD USING TYPtIUS GROUP (SOLUBLE) ANTIGEN.
2 21.65% OF THE VACCINATED POPULATION PER CENT
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- F -~~~~~~~~~ BOLIVIA-2 (1973-74): REACTIONS TO LIVING ATTENUATED E STRAIN TYPHUS VACCINE
EARLY REACTIONIS LATE REACTIONS TYPE OF REACTION (1 - 3 DAYS) (9 - 21 DAYS)
NO. % DURA- NO. % DURA- TION TION (DAYS) (DAYS)
SYSTEMIC HEADACHE 151 50.5 1.9 54 18.1 2.5 MYALGIA 89 29.8 1.6 12 4.0 2.8 ARTHPALGIA 77 25.7 1.6 14 4.7 1.7 ASTHENIA 111 37.1 1.8 34 11.4 2.1 FEVERISHNESS 101 33.8 1.7 13 4.4 2.5 FEVER (>370 C) 54 18.1 1.0 - - - CHILLS 37 12.4 1.4 10 3.3 2.5
LOCAL ERYTtHEMA 219 73.2 2.7 - - INDURATION . 224 74.9 3.2 - - VESICULATION 2 0.7 1.0 - - ESCHAR 2 0.7 1.0 - - REGIONAL PAIN 230 76.9 2.0 - - REGIONAL LYMPHADENOPATHY 7 2.3 2.0 - - NODE TENDEPRNESS 3 1.0 1.0 - -
TOTAL PERSONS EXlMIrNED: 299 (16% OF VACCINATED) BOLIVIA-2 (1973-74): REACTIONS TO TETANUS - DIPHTHERIA TOXOID'
EFARLY RFACTIONS TYPE OF REACTION (1-3 DAYS)
NO. % DURATION (DAYS)
SYSTEMíIC HEADACHE 86 36.3 1.7 MYALGIA 42 17.7 1.7 ARTHRALGIA 36 15.2 1.5 WEAKNESS 57 24.1 1.6 FEVERISHNESS 54 22.3 1.5 FEVER (>37 0C) - - CHILLS 15 6.3 1.0
LOCAL ERYTHEMA 119 50.2 2.4 INDURATION 133 56.1 2.9 VES ICULATION - - - ESCHAR - - REGIOMAL PAIN 142 59.9 2.4 REGIONAL LYMFPHADENOPATHY 5 2.1 1.0 NODE TENDERNESS 2 0.8 1.0
TOTAL PERSONS EXAMINED: 237 (12.7%) BOLIVIA-2 (1973-74): TYPHUS CF ANTIBODIES IN UNDIFFERENTIATED SAb1PLE 6-8 WEEKS POST-VACCINATION
AGE GROUP TOTAL TYPHUS GROUP CF (YRS) NO. NEG. POS. DOUBTFUL AC NO. % NO. % NO. % NO.
0-4 0 -
5 -9 7 3 42.9 4 57.1 0 0.0 0 0.0
10- 14 115 55 47.8 42 36.5 7 6.1 11 9.6
15- 19 70 25 35.7 32 45.7 4 5.7 9 12.9
20 - 29 64 24 37.5 22 34.4 3 4.7 15 23.4
30 - 39 47 16 34.0 21 44.7 6 12.8 4 8.5
40 -49 35 3 8.6 22 62.9 2 5.7 8 22.9
50- 59 26 9 34.6 11 42.3 3 11.5 3 11.5
60 - 29 3 10.3 17 58.6 3 10.3 6 20.7
TOTAL 393 138 35.1 171 L43.5 28 7.12 56 14.25