REVIEW OF STUDIES OF NATURALLY ACQUIRED IMMUNITY TO MALARIA IN IRIAN JAYA

REVIEW OF STUDIES OF NATURALLY ACQUIRED IMMUNITY
TO MALARIA IN IRIAN JAYA
J. Kevin Baird*, Ellen M. ~ndersen*,Michael J. Bangs*, Kurt or ens en*,
Suriadi ~unawan*.,Harijani ~ a m o t o * *Emiliana
,
'I'jitra0*,
Budi ~ubianto', Slamet Soenarno Harjosuwarno#

.

ABSTRAK

Penelitian mengenai kekebalan alamiah terhadapparasit malaria telah dilaksanakan sejak tahun
1987padapenduduk di daerah Arso, Irian Jaya bagiari Utom, sebelah Selatan kota Jayapura. Penelitian
tersebut telah menghasilkan infonnasi yang bennanfaat, baik untuk ilmuwan maupun untuk petugas
kesehatan masyarakat.
Kekebalan yang diperoleh terhadap parasitemia aseksual berkembang dengan cepat pada
tapi jauh lebih lambat pada anak-an& Namun gametositemia
trmmigran dari Jawa yang dewfalsipatum yang lebih tinggi ditemukan pada transmigran semua umur bila dibandingkan dengan
penduduk asli dun ha1 ini meningkatkan kemungkinan penularan malaria. Selain itu kekebalan yang
diperoleh juga akan meningkatkan efektivitas dari obat-obat standar untukpengobatan dart pencegahan

malaria v i v a dun falsipatunz. Setelah beberapa taliun kekebalan transmigran mendekati kekebalan
yang dimiliki penduduk asli.
Umur metupakan faktor yang penting untuk nienentukan efektivitas vaksin nialaria dun ha1
ini menjadi suatu aspek penting yang perlu diperhatikan dalatn strategi pengembangan vaksin. Tinggrggrnya
gametositemiapada transmigranperlumendapatperhatian danpengobatan gametositosidal (mis. dengan
primaquine) perlu dipertimbangkan.
Dan' sudut kesehatan masyarakat, penelitian itii menuttjukkan perlunya pemberantasan maluio
untuk transmigran dimulai sejak awal kedatatzgan mereka.

INTRODUCTION
Naturally acquired immunity to malaria
was first described in 1900 by the famous
German pathologist, Robert Koch, who
conducted hi landmark studies of acquired
immunity to malaria in Java. Koch conducted
microscopic examinations of blood films from

Naval Medical Research Unit #2, Jakarta
* * Communicable Diseases Research Centre, NIHRD, Jakarta
#

Irian Jaya Provincial Health Service, Jayapura.

BuL Penelit Kesehat 19 (4) 1991

people living in Batavia, Tosari, Sukabumi and
in the Ambarawa valley near salatigal. Koch
noticed that the prevalence of malaria in areas
where malaria transmission was seasonal or rare
was evenly distributed among age groups.
However, in the Ambarawa valley, where there
was heavy malaria transmission, the prevalence
of malaria diminished markedly with age. Koch

Review of studies of naluraliy .....I. Kevin Baird eta1

made a critical deduction -- prior exposure was
related to the distribution of parasites in the
community, i.e., there was acquired immunity
to malaria parasites. In the next year, Koch

confirmed his deduction with studies in New
~uinea~'~
Adults
' ~ . in Java and New Guinea
with life-long exposure t o heavy, but not
seasonal, malaria transmission were protected
from frequent and high grade parasitemia and
severe disease. The epidemiology of malaria
had never been understood before Koch s
immunity hypothesis. Rational analyses of the
epidemiology of malaria by christophers5 in
India and schuffner6 in Java followed Koch's
descriptions of natural immunity. History of
exposure defined immunity, and immunity
defined the distribution of parasites and
sickness in the community, i.e, the epidemiology
of the disease.
Naturally acquired immunity to malaria
remains a highly relevant research topic today.
2 approaches to

Good and ~ i l l e described
r~
development of vaccines against malaria
parasites; 1) understand the natural immunity
to malaria parasites and attempt to reproduce
it, or 2 ) attempt to induce a "supernatural"
immunity with the use of select combinations
of antigenic peptides, carriers and adjuvant.
T h e greatest advantage of a supernatural
vaccine is that it would presumably eliminate
or prevent infection, disease or its transmission.
The disadvantage of a natural vaccine is the
apparent lack of a sterilizing immunity, i.e., even
people with the highest degrees of natural
immunity occasionally have low-grade
asymptomatic parasitemia. On the other hand,
naturally acquired immunity to malaria clearly
works, whereas supernatural immunity remains
to be demonstrated. Regardless of which
a p p r o a c h is followed, a f u n d a m e n t a l

understanding of natural immunity is required.

2

However, naturally acquired immunity remains
a poorly understood process. Improving this
u n d e r s t a n d i n g h a s b e e n t h e focus of
immunologic studies of malaria conducted in
the Arso region.
The migration of nonimmune people from
more developed, less malarious provinces to
highly malarious, underdeveloped areas
presents many challenges to public health
workers. A parallel situation exists in the
development of relatively remote malarious
areas for tourism -- leisure tourists avoid
malarious areas. Public health attention is
often directed to the immediate concern of the
preservation of life and economic viability of
communities composed of people that are highly

susceptible to sickness and death due to malaria,
whether they be farmers or tourists. Scarce
public health resources are directed to these
new communities of highly susceptible
newcomers. The allocation of resources seems
proportionate to their relative susceptibility to
infection. T h e situation raises several
important questions for the public health officer
and policymaker: 1) What kind of malaria
control works best in new agrarian or resort
communities? 2) How long and to what degree
should those measures be applied? and 3) Who
is most susceptible to infection, and for how
long? The answers to these questions may be
addressed by studies of the development of
n a t u r a l l y a c q u i r e d immunity in whole
communities that lack prior exposure to'
endemic malaria.
The term "immunologic studies" is often
associated with basic laboratory studies of

antibodies, cytokincs, immune cells and
antigens addressing issues of molecular and
cellular biology. In the context of immunologic
studies in the Arso region of 1rian' Jaya, a
broader epidemiologic/public health definition

But. PenetiL KesehaL 19 (4) 1991

Review of studies of naturally

applies as well. The focus of the immunologic
studies in Irian Jaya has been the relationship
between duration of exposure to infection, age
of the host, and susceptibility to frequent high
grade parasitemia and severe symptoms8. This
is an area of mutual interest to the basic scientist
and public health strategist.
DEFINITION O F NATURALLY ACQUIRED
IMMUNITY
The term naturally acquired immunity to

malaria, hereafter referred to as NAI, may be
any phenomenon of immunity which develops
after exposure to infection. NAI usually refers
to diminished susceptibility to infection in
people. However, NAI may be any cellular or
molecular process which occurs after the first
exposure to the parasite, whether the process
is associated with protection or not (which is
not yet discernable). The distinction in the
application of the term NAI should be made
clear -- one is NAI at the organismal and
population level and refers to real protection
from infection, whereas the other is at the
cellular/molecular level and does not necessarily
relate to real protection. NAI is a general term,
and protective NAI refers specifically to
processes associated with demonstrable
protection from infection.
Protection from malaria in endemic areas
begins in the womb and continues to develop

throughout childhood and adulthood. Maternal
IgG, and perhaps priming of immune cells with
malaria antigen at critical periods of fetal
development, prepares the infant born to
endemic malaria. Before 1 year of life, this
protection wanes and the child begins a period
of 1 to 2 years of high susceptibility to illness
and deathg. Susequently, the child possesses
a so-called "anti-toxic"immunity where frequent

BuL Penelit KesehaL 19 (4) 1991

..... J. Kevin Baird eta1

and high grade parasitemia is tolerated with
relatively little discomfort. For example, a
non-immune adult may suffer severe symptoms
of malaria and be confined to bed for many
days with as few as 20 parasites per microliter
of blood. In contrast, a 4- year-old child may

have several thousand parasites per microliter
of blood and be laughing and playing in his
yard (personal observation) -- this is anti-toxic
immunity. At about age 5 there may b e
noticeably fewer and lower-grade parasitemias.
This trend continues gradually into adulthood
where parasitemias become infrequent and
g e n e r a l l y asymptomatic. D i m i n i s h e d
susceptibility to frequent and severe malaria as
a product of heavy exposure to malaria is
"protective NAI" as defined in this review.
THE MECHANISM OF PROTECTIVE NAI
Most investigators agree that the
mechanism of protective N A I is poorly
understood. However, most accept a model
for protective NAI which may be described as
t h e cumulative acquisition of protective
immunity9. That is, antigenic diversity in the
parasite drives host susceptibility for many
years, until finally the cumulative effect of heavy

exposure and clonal selection provides a
repertoire of immune cells which is sufficiently
diverse to defeat or suppress the parasite. This
model of immunity has been supported by the
consistent finding of age-related diminishing
susceptibility to infection among people living
in hyper and holoendemic areas. Serologic
studies have also shown increasing levels of
specific antibodies with increasing age.
However, recent studies of protective NAI in
the Arso region cast doubt on this modello.
Whether this model is accurate is a
question of significance for non-immune people

3

Review of studiea of naturally

trying to establish new lives in an endemic area.
Will adult newcomers require decades of
exposure to infection to reach the same level
of protective NAI in their native neighbors?
In fact, studies of protective NAI in newcomers
to the Arso region demonstrated that this
expectation is not true1'. Understanding
acquisition of NAI in transmigrants in Arso may
hold important clues to understanding immunity
to malaria parasites.

.....I. Kevin Baird era1

PROTECTIVE NAI IN THE ARSO REGION

Transmigrants from Java immediately
experience very heavy exposure to malaria
transmission when entering hyperendemic areas
like the Arso region of Irian Jaya (Fig.1).
Susceptibility to frequent and high grade
parasitemia seems uniform among the age
groups during the first few weeks of exposure.
However, an age-dependent protective NAI

PREVALENCE OF ALL MALARIA (96)

MONTHS IN IRIAN JAYA
Figure 1. Prevalence of all species of malaria in Arso PIR I1 in north eastern Irian Jaya among
people from Java who arrived free of malaria parasites. After 1year the prevalence
peaked at 70%. The dotted line represents the clearly temporary effect of mass
administration of chloroquine sometime between the 12th and 15th month.

Bul. Penelil Kesehal 19 (4) 1991

.....I. Kevin Baird a a l

Review olstudia of natural@

develops relatively quickly -- no later than 18
months, and perhaps even sooner (Fig. 2). The
diminishing susceptibility to infection with
increasing age appeared in measurements of
frequency of parasitemia, duration of parasitefree periods (Fig. 3), intensity of asexual
parasitemia, and frequency and severity of
I n all of these
symptoms (Fig. 4).
measurements, age-dependent protective NAI
was nearly parallel to that occurring among the

natives of Irian Jaya. Furthermore, humoral
immune responsiveness t o ring-infected
erythrocyte surface antigen (RESA) increased
proportionately with age (Fig. 5). Despite a
uniform 2 year period of heavy exposure to
malaria antigens among the transmigrants, the
acquisition of protective NAI was
age-dependent. In these studies, care was taken
to exclude innate characteristics of immunity
to infection by malaria parasites, for example

FOUR MONTH SPR (96)

I-

Transmigrants

- - - Natives
AGE (years)

Figure 2.

The slide positivity rate for Plasmodium faleiparum by active case detection during
a period of 4 months of surveillance in Arso PIR I in 1988. The transmigrants from
Java had arrived in 1986, and already demonstrated a distinct decreases in susceptibility to asexual parasitemia with age.

BuL Penelit Kesehat 19 (4) 1991

Review of studies of natural$

.....J. Kevin Baird eta1

MEDIAN WEEKS TO FIRST PARASITEMIA

-

Transmigrants

2-5

- --

Natives

6-10

11-15

AGE (years)

Figure 3. Each point represents the median number of weeks at which half of the subjects in
the indicated age and ethnic groups experienced their first asexual parasitemia by
P. falciparum during a four month period of biweekly surveillance. This period
represents the 19th to 23rd month of residence in Irian Jaya for the transmigrants.
The natives of Irian Jaya were far slower to become parasitemic, but the increasing
resistance to parasitemia with age was similar in both groups.

Bul. Penelil Kesehat 19 ( 4 ) 1991

Review ofstudies of naturally

..... I. Kevin Baird eLal

MEAN RESA ELISA O.D.

2-5

6-10

11-15

> 15

AGE (years)

Figure 5. The mean optical density (O.D.) values for an enzyme-linked immunosorbent assay
(ELISA) for antibody to ring-infected erythrocyte surface antigen (RESA) within
indicated age and ethnic groups. The rate of increase in O.D. with age was identical
in each ethnic group despite the great disparity in their cumulative exposure to
malaria antigen. The transmigrants had been in Irian Jaya for 19 months at the time
these serum samples were collected.

BuL Penelil Kesehal 19 (4) 1991

Review of studies of naturally .....3. Kevin Baird eta1

glucose-6-phosphate dehydrogenase deficiency
and hemoglobinopathies. At the time of these
s t u d i e s i n A r s o , relatively few s u c h
abnormalities were detected1'. Therefore, it
appears that transmigrants quickly (within 2 to
5 years)-develop a level of protective NAI which
is comparable to natives of Irian Jaya of the
same age.

immune responsiveness. For example, one
should expect the antibody titer in a child to
be lower than in an adult, even though they
may share an equal degree of exposure within
the past few months. This is the basis of the
recommendation to select a narrow age range
of a d u l t s f o r s t a n d a r d i z a t i o n of s e r o epidemiologic assays of malaria in lndonesials.

Protection is not the cumulative product
of many years of exposure. If this is true, then
the basis of childhood susceptibility t o
falciparum malaria is an inherent characteristic
of the host rather than the parasite. In other
words, antigenic diversity in the parasite does
not drive childhood susceptibility to infection.
Instead, childhood susceptibility is driven by
some characteristic of the acquired immune
system which changes with age.
This new model for protective NAI must
be borne out by studies in other populations
conducted by other investigators before it may
be generally accepted. Earlier studies have
shown a similar
but were
inconclusive. However, a recent study in Sri
Lanka showed age-dependent protective NAI
in people with only brief exposure to endemic
falciparum malaria 13.

Studies of protective NAI in Javanese
transmigrants a n d natives of Irian Jaya
demonstrated a rapid onset of protection from
frequent and high-grade parasitemia among
adults. Children remain susceptible, however,
no more susceptible than children native to an
endemic area. Asexual parasite counts and the
frequency of symptoms among those with
parasitemia were comparable among
age-matched groups of transmigrants and
natives after 18 to 22 months residence. In
contrast, the frequency and and level of
gametocytemia is remarkably greater in
transmigrants of all ages than among natives
of Irian Jaya (Fig. 6)16. Thus, transmigrants
may be reasonably expected to contribute
disproportionately t o the transmission of
falciparum malaria.

PRACTICAL ASPECTS OF NAI STUDIES IN
IRIAN JAYA

As Koch's hypothesis of immunity to
malaria led to the practical field of epidemiology
of malaria (malariometry), the studies of
protective NAI in Arso provide insight and
information of value to the public health officer.
Seroepidemiology of malaria, which can be
useful in certain settings in 1ndonesia14,depends
upon an appreciation of the relationship
between degree of exposure and humoral

But. Penelil. Kesehal. 19 (4) 1991

Immunity to malaria parasites plays an
important role in the responsiveness of atients
t o chemotherapy of the infectionIP. F o r
example, chemotherapy of chloroquinesensitive malaria in a non-immune patient
requires 25 mglkg chloroquine, whereas 10
mg/kg chloroquine has been considered
sufficient for residents of hyper to holoendemic
areas 18. In Irian Jaya, we have seen this
principle reinforced by several observations.
When Murphy and others screened for R vivax
resistance to standard therapy with chloroquine
in Arso, the vast majority of proven cases of

9

Review of studies of naturally .....I. Kevin Baird eLal

resistance occurred in very young children
(unpublished). The cumulative incidence of
chloroquine prophylaxis failure against I? v i v a
in among 24 Javanese transmigrants having just
18 months residence in Irian Jaya was 67%19
-- among 26 Javanese transmigrants of 45
months residence in a nearby village, the
cumulative i n c i d e n c e of c h l o r o q u i n e
prophylaxis failure was less t h a n 5 %

(unpublished). The rate of in vivo resistance
of rl falciparum t o standard therapy with
Fansidar differed dramatically among
transmigrants of 18 vs. 45 months residence in
Irian Jaya (Fig. 7)20. Thus, people having less
a c q u i r e d immunity a r e m o r e likely t o
demonstrate parasitemias which resist
standard curative therapeutic or prophylactic
regimens.

CURE RATE (%) - FALCIPARUM/FANSIDAR

18 months

45 months

Life-long

DURATION OF RESIDENCE IN IRTAN JAYA
Figure 7.

Resistance to Fansidar by P. falciparum seems profoundly effected by duration of
residence in an endemic area. Fourteen of 24 people with only 18 months routinely
failed to clear parasitemia within 7 days of therapy with Fansidar (58%), whereas 26
people of 45 months residence routinely cleared the parasitemia.

Bul. Penelil Kesehal 19 (4) 1991

Review, of studies of naturally .....I. Kevin Baird eta1

CONCLUSIONS
Endemic malaria profoundly effects
social and economic development. People are
reluctant to invest their futures in areas where
a life-threatening disease is common and
resistant to most known chemotherapies. This
attitude extends to the investment of capital in
agriculture, heavy industry, and tourism.
Where malaria cannot be eradicated or even
effectively controlled, alternative solutions must
be offered to address the fears of well-informed,
sensible people. In short, living with malaria
and minimizing its social and economic impact
requires a clear understanding of its distribution
in defined populations, and knowing the
patterns of susceptibility in these communities.
Immunologic studies of malaria in Irian
Jaya have demonstrated that alternative
solutions may be possible to diminish both the
risk and fear of malaria. The farmer or investor
maybe assured that non-immune adults exposed
to endemic malaria may acquire appreciable
degrees of protective immunity within a couple
of years. Similarly, resistance to standard
antimalarials may be less pronounced after the
first couple of years of exposure. Strategies
of control for the initial period of susceptibility
may be developed by forecasting patterns of
immunologic susceptibility and drug resistance
in a population. For example, it may b e
p r e d i c t e d that newcomers will b e most
susceptible to sickness, gametocytemia, and
resistance t o therapy with chloroquine.
Therefore, one may direct chemotherapeutic
control measures in view of these realities, e.g.,
temporary administration of primaquine for
prophylaxis in newcomers may protect against
dangerously high initial infection rates by killing

12

the liver stage of the parasite (prophylaxis), and
by sterilizing gametocytes in those who were
only partially protected. Later, as people
become accustomed to malaria and develop
improved NAI, chloroquine or other standard
antimalarials may suffice for protection from
symptomatic malaria. All of these possibilities
require careful and certain demonstrations of
medical, logistical and economic utility. For
example, administration of primaquine on a
large scale carries with it a risk of serious side
effects in some people, as well as the danger
of development of parasite resistance t o
primaquine. The administration of primaquine
for long term prophylaxis has not yet been tried
in people native to endemic areas.
Tourists may visit endemic areas with high
levels of parasite resistance to antimalarials.
They probably know something of the malaria
situation and may have access to reliable
information about drug efficacies. These
well-informed tourists confidently use a regimen
of prophylaxis known to be effective in the area.
In contrast, the poorly informed tourist may
carry chloroquine or nothing at all, and he
represents the greatest danger to the local
tourist industry by being at high risk of sickness
or death due to malaria. The presence of
non-immune newcomers to Irian Jaya presents
an opportunity to understand resistance to
antimalarials in the most susceptible group of
people, and to evaluate alternative therapies,
i.e., offer solutions to endemic drug resistance.
I n summary, the level of acquired
immunity among residents of an area is an
important consideration in understanding the
epidemiology of the parasite, as well as in
d e v e l o p i n g s t r a t e g i e s of control,
chemoprophylaxis and chemotherapy of the

Bul. PeneliL KesehaL 19 (4) 1991

Review of studies of naturaliy ..... I. Kevin Baird eLal

disease. I n addition, the mechanism of
protective NAI remains an important issue of
basic immunologic science and, ultimately,
malaria vaccine development. For NAMRU #2
and collaborating Ministry of Health agencies,
Irian Jaya has been the ideal site to address
these important issues. Irian Jaya bears the
burden of hyperendemic malaria with many
non-immune people, and severe resistance to
antirnalarialsl9. In addition, the punctulatus
complex of vector species are notoriously
difficult to control in places like the Arso
region19. So far, Irian Jaya is the only place
in the world where resistance to chloroquine
byE vivm appears to be endemic. Finally, Irian
Jaya is one of the few areas of the world where
all 4 species of malaria occur together2'. Irian
Jaya offers rare medical research opportunities
that can be exploited to help deal with the severe
malaria problem in Indonesia and other tropical
areas.
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