VACCINATION DHF 

PROFIT OR LOSS?

T. Mudwal

Healthy or sick individual as we know it is at the interaction between the human immune system, the environment and agents (bacteria / virus / antigen). To make humans still healthy, the immune system or immunity must be good, the environment must support the immune system in order to remain well and antigens as well as all the factors that support these antigens must be eliminated.

If the environment and agent are hard to be corrected, then the increase in the immune system must be done so that there is no illness. Immunization or vaccination is an example of this. But apart from the classical theory of the occurrence of illness in humans as described above, humans can also become ill if their immune systems are too reactive (hypersensitive). Where in such circumstances the immune system provides an overreaction to an agent or certain microorganisms. So it’s not the lack of an immune system that causes people to become ill, but errors in responding an agent that enters the body, as the basis of the occurrence of illness.

With the above information, it is clear that before giving additional strength to our immune systems, it should be clear to us first or  agreed upon first or first sought with the most powerful theory that can explain why a person becomes ill (pathogenesis and pathophysiology).

For DHF, in principle, there are 3 theories that explain why the person is exposed to DBD:

1. Theory of the malignancy virus

Dengue virus is in colaboration with poor ecosystems, and will cause the dengue virus to get stronger, multiply, and spread throughout the country’s territory and then beat that person’s immune system. Poverty, low education, will add up quickly to the region or the country to be branded as a country or region of dengue hiperendemic. To quickly reduce many of the sufferers of DHF, then one must quickly improved antibodies and the antibody is expected to last long. It was hard to make corrections to the environment and defeat the dengue virus. Immunization or vaccination, that’s the most appropriate solution and fast.

Infusion of fluids and close observation are the primary therapy in patients affected by dengue fever based on this theory.

2.Theory of the malignancy virus combined with wrong response to the immune system during the enterance of dengue virus in the body (Theory of Halstead).

The body can manage to overcome the any dengue infection even the malignant ones, as long as there is no non-neutralizing antibodies. Non-neutralizing antibodies, are newly-formed when the body is infected with viruses of a different serotypes (Secondary Heterologous Infection Theory). So indirectly on this theory there is no term of dengue virus are malignant or not malignant. All the dengue virus are malignant if it succeed in entering the target cells, replicate and increase strength in the target cells are then release again into the blood. Non-neutralizing antibodies, spur the entry of the virus into target cells.

So based on this theory, what if someone is infected with one kind of virus alone, either one time or continuously, the person would never be ill of DHF (occurring lifelong immunity against that virus / forming a lifelong neutralizing antibodies against thatdengue virus). However, immunity against a virus also triggers the formation of both a non-neutralizing antibodies when the body is infected by dengue virus of another type. So to reduce morbidity and mortality of DHF, the fastest way is to provide immediate vaccination of all four dengue virus serotypes (because there are four serotypes of dengue virus) in hopes to directly increase the neutralizing antibodies against all four dengue virus serotypes. Or prevent the occurrence of non-neutralizing antibodies in case of dengue virus infection, one by one. This theory is now widely used around the world.

The main therapy for a person who is infected by dengue based on this theory is the same as the theory of malignant virus which is fluids resustitation and close observation.

3.Wrong Immune response of the individual as the main basis of dengue illness (Type III Hypersensitivity theory T. Mudwal/ www.dhf-revolutionafankelijkheid.net )

Based on T. Mudwal this theory states:

a. Not all people or race will be exposed to dengue.

DHF mainly on Southeast Asia and Western Pacific (however today, dengue fever has struck nearly 100 countries around the world and a variety of races). Observations over 15 years of DHF patients, showed ethnic of Arabs, Chinese, caucasian origin, are very rarely affected by dengue, even when there was an endemic. Experiences at school in the RSCM, working in the Pacific Caltec Riau and working at this moment, is the basis for this claim besides that there facts are on this earth in the form of written journals.

b. Bad immunity, but  low symptoms.

If we used a benchmark that severe dengue is someone with a history of fever ≤ 7 days, presence of shock, shortness of breath, hepatosplenomegaly, severe bleeding /DIC and platelets ≤ 20.000/mm3, then roughly calculation there are more common in people with good nutrition, have a good immune system rather than a person with malnutrition or those with age> 60 years, which is roughly with a bad immune system. It is difficult for a HIV patient who clearly have a poor immunity to be infected by dengue. Dengue fever can only infect  HIV patient when CD4 count is above 200 cel/mm3. Or the immune system are still pretty good.

c. Error response of our immune system.

Just like Halstead, the antibodies are not capable of neutralizing antibodies (non neutralizing antibody is formed). But T. Mudwal does not say it is non-neutralizing antibodies. T. Mudwal says it is an imperfect Ig G/IgM (because immunologically, our immunoglobulins are IgA, IgE, IgD, IgM, IgG). The formation of imperfect Ig G/IgM is because of the sensitivity of the body against dengue antigens, so that plasma cells which are not old enough to make antibodies, will also  make antibodies. This is evidenced by the discovery of blue lymphocyte plasma cells (LPB) in patients with DHF. Only DHFcan cause the LPB cells to be seen in acute phase (<7 days of illness). There are even studies that say, LPB was present in 98% of DHF patients. In healthy people LPB is not visible at all (0%). Ig G/IgM as a result of not fully formed, the virus managed to escape from the bonds of Ig G/IgM and enter the target cells. So at the imperfect Ig G/IgM does not happen to spur the virus to enter the target cells, as proposed Halstead. Association of antigen and antibody persists, but its binding are weak.

Because the target cells from dengue virus is our own soldiers cells (monocytes, macrophages and Kupffer cells), the immune complexes formed, both between perfect Ig G/IgM with antigen and imperfect fraction Ig G/IgM with antigen failed to be destroyed by our troops so that the cells spread throughout the body ( capillary wall, platelets, bone marrow, liver, spleen, brain, heart, eye, and so on). The return of normal function of our soldier cells or the arrival of troops from its headquarters in the normal bone marrow will lead to the destruction of these immune complexes. The degree of severity of DHF depends on the location and number of immune complexes that are destroyed. For that reason T. Mudwal said the basis of pathogenesis and pathophysiology of DHF is Hypersensitivity reaction of the immune complex (Type III Hypersensitivity reactions).

Presence of large amount of immune complexes can trigger a disturbance in the regulation of our immune system. So it can happen that the body’s cells that should not have be destroyed, were destroyed. The existence of an autoimmune reaction against platelets (positive platelet antibody) is a example of it. This disturbance could even happen for life, so that people become ITP (a lifetime oflow platelet). Patients with SLE must be considered to be likely triggered by dengue. Healing in the damaged organs may occur imperfectly. Aplastic anemia, stroke, impaired vision due to retinal damage and so forth are possible.

Other things that proving if Hipersensitivity is the cause of DHF disease is the triumphness in giving the drugs in order to suppress the hypersensitivity reaction (immunosuppressive cortico steroid) by Waly et al (Indonesian University Medical Faculty, 1997), Hendarsih et al (Padjadjaran University Medical Faculty, 2004) and Futrakul et al (Thailand,1987).

Based on the information,a new great DBD reaction will occur if the incoming antigen are polynomial, which formed many imperfect antibody, macrophages infected with dengue is invalid due to its huge quantity, the location and number of immune complexes that are destroyed. Virus infection in a small amount of one kind of virus alone usually may not pose a Type III Hypersensitivity reactions. Or it could give a reaction but usually mild (fever, headache, muscle pains, vision problems, etc.). But it could also deliver a severe reaction as described above, the quantity of antigens are abundant, or tend to be super antigen. Or individual is too sensitive hence the imperefect IgM antibodies which are formed are in large amount or genetic mutations occur either from the virus or the individuals. Difference in the theory T. Mudwal and Haslstead, when Halstead said that one kind of viral infection the first time will result in lifelong immunity then T. Mudwal said no. There is no lifelong immunity in hypersensitive people. The reaction depends on what has been described above. This was the true basis of T. Mudwal to say why the primary infection may give clinical symptoms. One thing that is difficult to answer Halstead. Hence came theantibody dependent enhancement theory to explain why the primary infection can cause clinical symptoms. Where based on this theory, the primary infection reaction is because of the non-neutralizing antibodies from the mother. So if there is infection by dengue virus it is because there was an infection of a different type on his mother. Meanwhile, according to T. Mudwal children from 0-4 months are going to get antibodies from their mothers in accordance with the dengue virus that have been infected by his mother. But after that, it is because of genetics itself. Hence formed sensitive IgM-. After six months of forming the sensitive IgG. So, antibody towards Dengue virus which come from the children’s mother, only last for 6-9 months. After that DHF disease which happened then is because the sensitivity of IgM and IgG those children itself. Sensitivity is genetic. Just like Halstead, dengue virus infection from a second time in small quantities and the same virus, may not happen but the reaction that occur does not give lifelong immunity. But if there is a viral infection of a second time from a different virus type, although in small quantities is more dangerous than the same virus infection in large numbers. This is because different viruses will provide a stronger stimulus for the occurrence of errors immune response than the same virus. But when a virus infected again by the third or fourth (by other dengue virus) then the reaction will occur much lighter because of some of the properties of the virus has been recognized by our immune system (because all of them is dengue virus).

If we consider this theory as true, vaccination that already is done towards monkey can’t become a standard to human being. Illness which happened to monkey is not because hypersensitivity but because of clash between virulence virus with monkey’s antibody. Truthfully, Dengue virus is not made in purpose to attack human. If now we found many humans have DHF from Dengue virus this is because human hypersensitivity or genetic mutation from virus or human itself or the human movement. (transportation, urbanization, etc).

Based on information above there isn’t any eternal immunity in Hypersensitivity type III theory. So, to avoid someone from DHF, is not by giving vaccination but the solution is environment improvement and healthy lifestyle is the key to exterminate DHF even it’s very difficult to do. Even when we still want to give vaccination the aim of that is not to elevate antibody. Low dose antigen giving which given continuously/ simultaneously (booster) is to make the person not too sensitive towards antigen (desensitization).  And based on Hypersensitivity type II theory, very low dose vaccination with one by one virus and also with continuous/simultaneously booster (>3 times) is more safe rather than tetravalent vaccination from Dengue virus. But it’s clearly this method is very time and fund consuming. If we still want to give tetravalent vaccination (4 in a time), the dose vaccine must be very low. Even, lower than monovalent vaccination. The consequence taken from this method desensitization towards 4 type of serotype virus is very time consuming (we don’t know when). The way of thinking like that is only coming when we stick to Hypersensitivity type II theory as the basic. Even based on HS type III theory, antibody that we hardly get before will also disappear if booster is not done continuously/simultaneously. At the end without booster vaccination, antibody that stays in our body is only antibody that comes from mosquito vaccination.

 

DISCUSSION ON VACCINE TRIALS

In Thailand since February 2009 to March 2011 there have been done three injection of tetravalent vaccine. They hope that there will be immunity against four dengue virus serotypes. Where the injection was given to 4000 children aged 4-11 years. They are strictly monitored for 28 days after injection, and claimed  there was no side effects (World’s first dengue vaccine shows promising results; By Pongphon Sarnsamak; the Nation; Published on June 11, 2011).

On this basis Indonesia, in thiscase the ministry ofhealth, is willing to proceed to phase three trials of dengue vaccine made by Sanovi Aventis in Indonesia. Indonesia it will be tried on 2000 children aged 2-14 years. Injections will be given 3 times of the month to 0, 6 and 12. After that all the children of volunteers will be monitored for the next 5 years, whether or not immune to dengue. Then be judged by how well its neutralizing antibodies against dengue virus 1, 2, 3, 4 if they are still there or had disappeared.

I personally, do not agree with Indonesia participation in this next dengue vaccine trials from Aventis Sanovi. Actually, what is the relevance on the safety of the side effects after injection of the vaccine? If 28 days after injection the children platelets decrease from 200.000/mm3, then dropped to 150.000/mm3 at day 28 after injection, is it not considered harmful side effects? Normal platelets, does range from 150,000 to 350,000/ mm3. The ability of the bone marrow to make platelets daily maximum can reach 240.000/mm3. When a healthy child platelet count is 200.000/mm3 before the injection is then dropped to 150.000/mm3 at day 28 after injection,does it not shows that there is an existence of something as the cause. Minimal defect in the bone marrow or minimal occurrence of enlarged spleen (which was not detected even ultrasonogrphy) can lead to things like that. And the child will certainly have no complaints, but it is potentially dangerous side effects. It should be on day 28, the child platelets returns back to the state ranging 200.000/mm3. Similarly also is the presence of fever after vaccination. Fever that occurs (> 37.50C) must be considered that the child is suffering from dengue until proven otherwise or it is just a normal immunological reactions caused by the vaccination. When the child with a fever after the injection was obtained a positive torniquet test (Rumple Leed), or there is a significant fall in platelet count (> 50.000/mm3) or the Ht / Hb> 3 times or the lymphocyte count <20% or monocyte count <3 % or discovered forms of abnormal lymphocytes (BluePlasmalymphocytes)> 1% then the children must be suffering from dengue and must be strictly observed. Because DHF is unpredictable.

In the study of the administration of vaccine dengue 2 towards 10 volunteers aged 18-30 years all obtained the picture of an abnormal lymphocytes (which I believe is LPB) and a decrease in the number of lymphocytes on day 6 or day 10 after injection (WHO’s Efforts for the development of a dengue vaccine; Sutee Yoksan #; dengue Bulletin – Volume 32, 2008). This means that up to 10 days after injection of the vaccine the children still suffers from DHF. On other journals found that administration of a vaccine dengue 2 towards 38 volunteers turned out to symptoms of fever reaches 10% (Dengue Vaccine Development – 2; Dr. Emilliana Tjitra, MSc; No PowerPoint. 50.1988). which means that after vaccination people can be exposed to dengue as I have described above.

Although 4000 children in Thailand reported to be fine, after 2-year trial of the vaccine program, it does not mean that Indonesian children will have the same response to the vaccine. Tribes – race  play a very important role, 1% or 20 people from the 2000 children suffer from fever and diagnose as dengue as the criteria that I have explained above, then the vaccine can not be used. Because the vaccine will be given to tens of millions of Indonesian children. With descriptions like the above, Indonesia should not immediately agree to participate in phase 3 trials of the vaccine that Aventis Sanovi. Let us just see the results of vaccination from Thailand.

Professor Sri Rezeki, a vaccine researcher who was the Chairman of the Task Force on Immunization of the Indonesian Doctors Association, said that Sanovi Aventis vaccine trials in phase 1 and 2 are shown to provide protection to children and adults from the attack of dengue (Tempo online; waiting three decades; 06 June 2011). If the injection of the vaccine only provides immunity for 18 months or 2 years or only at the time of receiving the vaccine, then that is a useless action. Thailand began to give vaccinations in February 2009 and ended in March 2011. They claim that the antibodies against the four serotypes of dengue virus were present in all the vaccinated children. In June 2011 (three months after the end of injection) they claimed that it has been getting tremendous results. For me, the result seems totally meaningless because it is only been 3 months after vaccination. Still be obtained even for antibodies to four serotypes in a year ahead, it could still not be something unusual, because it is only 1 year after vaccination. Where as Thailand believes that if  the next year the four antibody serotype are obtained in the body, then the dengue vaccine is considered successful and it should be spread through out the world.

The success is not exposed to dengue infection or its still positive neutralizing antibody or IgG perfect antibodies for 3 or 5 years after the final vaccination, and then should be vaccinated again, is not a success. It is a waste of government spending.

Based on the theory of type III HS, desensitization which is considered vaccination, will only last as long as the dengue virus antigen are kept supplied continuously or booster. If an injection or booster was stopped, then one will come back to being hypersensitive. Because  hypersensitivity is genetic. Experiments on the provision of a dengue vaccine (dengue 2) was acquired immunity which lasted only three years after the last injection of vaccine (Dengue-2Vaccine Development; Dr. Emilliana Tjitra, MSc; Cermin Dunia Kedokteran. No50.1988). Shaping immunity against the four serotypes is more difficult than in the form of immunity to one dengue virus serotypes. In the calculations on paper, I predict immunity against the four serotypes which was boasted by the Thai scientists will expire two years after the last injection (March 2013). Even according to their reports after the end of injection (March 2011), 73 children(1.8%) of the  4000 volunteers, viremia are still found in the blood. This means that after 2 time of injection prior did non give any result.

Viewed from the standpoint of the HS theory of type III, immunity of dengue virus 1,2,3,4 in the sense that the person does not suffer, fever, plasma lekage, thrombocytopenia, etc., can only occur when dengue virus was injected (whether vaccination from health workers or by mosquitoes) are few. When in large numbers, or if there is a genetic mutation of the dengue virus antibodies against the four serotypes than the hard work have been for nothing, for example in the state of dengue outbreaks. In this such outbreaks viremia and invalid from of macrophages still occur, to further spread immune-complexes and the destruction of immune complexes which can be fatal (www.dhf-revolutionafankelijkheid.net). What we must watch out for is the occurrence of dengue fever attacks without having obtained fever. Stroke, acute MCI, conjunctifities, severe arthritis, severe Dyspepsia syndrome, severe acute diarrhea and so on, could have occurred due to dengue infection obtained without fever. In such circumstances the diagnosis of dengue infection as the cause, are neglected.

(www.dhf-revolutionafankelijkheid.net).

CONCLUSION

Hopefully this article can clarify all of us, that DBD vaccination has more disadvantage than benefits. And may we all do not imitate Thailand scientists who says that vaccination is the most appropriate solution and quick in dealing with dengue in Thailand, no matter whatever the cost to be incurred by the country (World’s first dengue vaccine shows promising results; By Pongphon Sarnsamak; the Nation; Published on June 11, 2011).

And in the end may Allah Almighty and Most Clever and Strong provide guidance and courage to us all in taking the right decision