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Jet Injector and Vaccination

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Jet Injector and Vaccination Powered By Docstoc
					Virgilio Vinas, MD, MPh, PhD
clarityeye@msn.com



Framework for non-inferiority study on Pentavalent DTP+HB+Hib
from Bio-manguinhous using intradermal DSJI-PATH device and
subcutaneous Jet Injector-needle free injection.
Abstract
The DTP+HB+Hib Pentavalent has been developed following recommendations of the
World Health Organization for the introduction of hepatitis B (HB) and Haemophilus
influenzae type b (Hib) vaccines into routine childhood vaccination programs advantage
to combining childhood vaccines include reducing the number of visits, injections and
patient discomfort, increasing compliance, optimizing prevention. In 2009 Brazil applied
15,207 doses subcutaneous at 0.5 mL. For Pentavalent manufacture by Biomanguinos at
a price between $3.20-$3.50 per doses. Measurements for increase vaccine opportunities
will be important in terms of reducing the amount of vaccine/doses and get the same
immunization quality than conventional vaccination, increase the number of vaccination
in a short period of time using jet injector for intradermal vaccination, always reducing
the chance of disposable materials needles and syringes to reduce health problems and
increase health/life cost.

Intradermal administration of antigens
Intradermal administration of antigens is expected to facilitate their exposure to antigen-
presenting cells, such as macrophages and dendritic cells, which are present at higher
levels in skin than in muscle. (1) Therefore, as compared with intramuscularly
vaccination, intradermal vaccination may induce similar serum antibody responses with a
smaller quantity of antigen. The intradermal route has been evaluated for influenza,
rabies, and hepatitis B virus vaccines. (2,3,4,5), DTP-Hib-HB (Am J Public Health 1981;
71:1040-1043), the resulting immune response when vaccine antigen is introduce into the
skin upon stimulation keratinocytes can produce proinflamatory cytokines (interleukin 1),
the microorganism previously are engulfed by phagocytes cells like macrophages, but
evade the normal intracellular mechanisms that should destroy them acting as class II
antigens CD-4 of the macrophages, CD4+ T cells respond to these release. Any skin cell
express class I histocompatibility molecules at their surface, these can display antigens
fragments of viral components as class I antigens CD-8, CD8+ T cells that can bind to
these can destroy the cell.
In a series of tests, the Brigham and Women's Hospital researchers in Boston also found
that the memory of T-cells — the cells that mount an immune response against invading
viruses — may be more important than the antibodies generated by injected vaccines. T-
cells are located in lymph nodes and blood, as well as in peripheral tissues such as skin
and lung. "This research illustrates the remarkable capacity of the most superficial layer


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of skin to generate powerful protective immune responses after vaccination," study senior
researcher Dr. Thom Newsinator CMS (v1.0a) as Kupper, chairman of the dermatology
department at the hospital.
The intradermal adjuvants are used in the manufacture of intradermal vaccines for
humans, and in the intradermal treatment of humans like saponin and sterol formulated in
a liposome, or using aluminum based minerals (generically called Alum). Furthermore
the efficacy of adjuvants varies depending on the target compartment in a subject for the
delivery of immunogenic compositions, and thus each adjuvant must be validated
according to the composition's contemplated target compartment. Whereas a number of
adjuvants or potential adjuvants have been found and validated for spaces other than the
intradermal compartment, e.g., intramuscularly, intravenous or subcutaneous, prior to the
instant invention there were few known adjuvants with efficacy in the intradermal. (6)
The intradermal injection with lower amount of doses suggest between 2 and 19 %
additional vaccine doses per vial. There is an extensive literature of vaccination by
intradermal (ID) injection (Mantoux method or needle-free jet injector) of reduced
antigen mass compared to full doses by subcutaneous (SC) or intramuscular (IM) routes
of administration. Excellent results for rabies vaccine by the ID route are applied widely
in developing countries, which cannot afford full doses of modern tissue-culture
vaccines. For influenza, reports since the 1930s generally support comparable
immunogenicity by ID method. Inactivated polio vaccine (IPV) administered by this
route has shown promising results and may facilitate eradication once oral polio vaccine
(OPV) is abandoned for epidemiological reasons. On the other hand, mixed to poor
results have been found among reports of administering hepatitis B and measles vaccines
by the ID route. To date, there has been only one report of ID vaccination with any
polysaccharide vaccine, traditional or conjugated, in this case with good results for
meningococcal A antigen. Reduced doses administered by the conventional IM or SC
routes, however, were found immunogenic for conjugated Haemophilus influenzae type
B (HIB) vaccine, studied for cost-saving potential in developing countries. (7)
Recent studies of ID administration of trivalent, inactivated influenza vaccine by Belshe
and Kenney reached the same conclusions although again, the vaccine doses were not
directly comparable between the two routes of administration tested (6 µg/antigen ID vs.
15 µg/antigen IM). Notably, Belshe’s results did indicate that in individuals older than
60, the H3N2 antibody responses following ID administration were less than those seen
in the IM group (no differences were seen in the younger cohort or for the other two
antigens in the older group). Both studies also documented more frequent but transient
mild local reactions following ID administration.
Intradermal injections are usually administered on the volar surface of the forearm. With
the bevel facing upwards, a 3/8--3/4-inch, 25--27-gauge needle can be inserted into the
epidermis at an angle parallel to the long axis of the forearm. The needle should be
inserted so that the entire bevel penetrates the skin and the injected solution raises a small
bleb. Because of the small amounts of antigen used in intradermal vaccinations, care
must be taken not to inject the vaccine subcutaneously because it can result in a
suboptimal immunology response.

Consequently, it has been proposed that the skin in particular should be an anatomical
site capable of stimulating potent immune response. For these reasons:
-Delivery of antigens to the skin (i.e., the dermis, epidermis, or both), as opposed to


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The muscle or subcutaneous tissue, could result in quantitatively or qualitatively
Superior immune responses.
-An equivalent or non-inferior immune response to that seen following SC or IM
Injection might be induced by delivery of a smaller quantity of antigen to the dermis,
i.e., be dose sparing. (WHO-PATH “Intradermal Delivery of Vaccines”, August 27,
2009).

Injections and Needles
Injectable immunobiologics should be administered where local, neural, vascular, or
tissue injury is unlikely. Use of longer needles has been associated with less redness or
swelling than occurs with shorter needles because of injection into deeper muscle mass.
Appropriate needle length depends on age and body mass. (8)
Injections that harm the recipient, the provider, or that result in waste that is dangerous
for other people are regarded as unsafe and can cause disease, injury and death, from 12
billions injections administers each year 6 billions are unsafe and 1 billion injections are
for immunizations (Jordar L et al, Vaccine 2002; 19; 1594-1605). In a year unsafe
injections may be responsible for 8 to 6 million cases of Hepatitis B, 2 to 5 million cases
of Hepatitis C, 80 to 160 thousands of HIV and other of Malaria, bacterial, fungal (Kane
A et al, Bulletin of the WHO, 1999; 77; 805-807).
There are close to 21 million cases of HBV, HCV and HIV infections attributable to
unsafe injections in the world yearly, the cost of medical care of the cases is estimated at
about USD$600 millions mainly in poor countries, unsafe injections constitute a public
health issue (Miller M, Pisani E, Bulletin of the WHO, 1999; 77; 808-811). Victims of
unsafe injections due to syringe and needle reuse or careless health worker injection
practices.
Seven types of injection devices for their risks of iatrogenic transmission of blood borne
pathogens and their economic costs in sub-Saharan Africa were investigated, founded
resterilizable and disposable needles and syringes had the highest overall costs for device
purchase, usage, and iatrogenic disease: median US$ 26.77 and US$ 25.29, respectively,
per injection from the societal perspective. Disposable-cartridge jet injectors and
automatic needle-shielding syringes had the lowest costs, US$ 0.36 and US$ 0.80,
respectively. Reusable-nozzle jet injectors and auto-disable needle and syringes were
intermediate, at US$ 0.80 and US$ 0.91, respectively, per injection. ( Donatus U
Ekwerme, Bruce G Weniger, Robert T Chen, Model-based estimates of risk of disease
transmission and economic costs of seven injection devices in sub Saharan Africa, WHO
Bull World Health organ vol.80 no 11 Genebra Nov 2002).

Jet Injectors
Giving vaccines without needles (needle-free vaccine delivery) may be better than giving
them using a needle for many reasons. (9)
Needle-free injectors for medical use is a recognized consensus standard ISO
21649:2006, Device Class II, 510(k) type submission.
 One method for giving shots without needles Jet injectors (JIs) are needle-free devices
that drive liquid medication through a nozzle orifice, creating a narrow stream under high


                                                                                           3
pressure that penetrates skin to deliver a drug or vaccine into intradermal, subcutaneous,
or intramuscular tissues. Increasing attention to JI technology as an alternative to
conventional needle injection has resulted from recent efforts to reduce the frequency of
needle-stick injuries to health-care workers and to overcome the improper reuse and other
drawbacks of needles and syringes in economically developing countries. JIs have been
reported safe and effective in administering different live and inactivated vaccines for
viral and bacterial diseases.
The immune responses generated are usually equivalent to, and occasionally greater than,
those induced by needle injection. However, local reactions or injury (e.g., redness,
indurations, pain, blood, and ecchymosed at the injection site) can be more frequent for
vaccines delivered by JIs compared with needle injection. (10)
Certain JIs were developed for situations in which substantial numbers of persons must
be vaccinated rapidly, but personnel or supplies are insufficient to do so with
conventional needle injection. Such high-workload devices vaccinate consecutive
patients from the same nozzle orifice, fluid pathway, and dose chamber, which is refilled
automatically from attached vials containing <50 doses each. Since the 1950s, these
devices have been used extensively among military recruits and for mass vaccination
campaigns for disease control and eradication. An outbreak of hepatitis B among patients
receiving injections from a multiple-use--nozzle JI was documented and subsequent
laboratory, field, and animal studies demonstrated that such devices could become
contaminated with blood. (11)
Years ago, people got shots using jet injectors, but these older devices reused the same
"nozzle" or hole through which the fluid was forced. Newer jet injectors, use disposable
cartridges to hold the vaccine. So, the only thing that touches the subject’s skin is his or
her own cartridge, which gets thrown away after injection. (12)
In the resent years Jet Injectors has been used in several clinical studies in vaccines
immunization:
1.       Clinical immunogenicity of measles, muSARNO Mark J. (1); BLASE Erich (1);
GALINDO Nelly (2); RAMIREZ Roberto (2); SCHIRMER Carl L. (2); TRUJILLO-
JUAREZ Daniel F. Mumps and rubella vaccine delivered by the Injex jet injector:
comparison with standard syringe injection:
No significant differences in immunogenicity were found between groups receiving the
vaccine via the jet injector or the needle syringe at any time during the follow-up (P >
0.05). Injection pain scores were not significantly different between injector types (P >
0.05). Conclusions. Conclude that the Injex jet injector can safely and effectively deliver
the measles, mumps and rubella vaccine. This device therefore provides an alternative to
standard needle injection and a methodology that might reduce the risk of needle stick
accidents.
2.       Kenneth Mc Intosh, Inara Orr, Marry Andresen, James H Arthur, Gordon J
Blakeman. Response of Normal Children to Influenza A/New Jersey/76 Virus Vaccine
Administered by Jet Injector:
 Ninety-seven children six t0 10 years old received monovalent influenza A/New
Jersey/76 virus vaccine by jet injector. Comparison with groups receiving vaccine IM
revealed that local reactions (tenderness and erythema) were more frequent and more
severe in the group vaccinated by jet injector. Antibody response, however, was similar
for all groups’ immunization.



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3.      , J. P. Stanfield, P. M. Bracken, K. M. Waddell, D. Gall, r Med J 1972; 2:197-
199 (22 April), doi: 10.1136/bmj.2.5807.197. Difteria-Tetanus-Pertussis Intradermal Jet
Injection.
 An intradermal jet injector was used to administer combined diphtheria, tetanus, and
pertussis (D.T.P.) vaccines to infants aged 2 to 12 months. A second dose was given one
month after the first and a third six months after the second. Each dose was considerably
smaller than the standard intramuscular dose. Blood samples taken one month after the
third dose showed a satisfactory diphtheria and tetanus antitoxin response in all but a few
cases. The antibody response to the pertussis component was not examined. Reactions
were insignificant. Intradermal jet injection is proposed as a cheap, extremely rapid, and
effective technique for D.T.P. immunization, especially suitable for use in remote areas
where trained staff and facilities are few and many children require
immunization.(13.14,15)
Others clinical trials including jet injectors are FDA registered:
NCT00386542: Needle-free Jet Injection of Reduce dose, Intradermal, Influenza Vaccine
6-24 month.
NCT00987350: Safety Study Seasonal Influenza Vaccine by Jet Injection


DTP+HB+Hib Pentavalent combination vaccines for childhood
Immunization
Vaccination is one of the most valuable and cost-effective strategies available to
medicine in the battle to prevent and control infectious diseases. It is considered to be one
of the ten greatest public health achievements of the 20th century . In the Americas,
vaccination has brought about the eradication of smallpox in 1970 and of polio in 1991;
the interruption of indigenous measles transmission in 2002; and the lowest numbers of
reported cases of congenital rubella syndrome (CRS) and neonatal tetanus at the onset of
the 21st century .(16)
More recently, additional combination vaccines have been licensed and introduced into
the immunization schedule of children in the United States, including: diphtheria and
tetanus toxics and acellular pertussis vaccine (DTaP); DTwP-Haemophilus influenzae
type b (Hib) vaccine (DTwP-Hib); DTaP-Hib; Haemophilus influenzae type b conjugate
vaccine-hepatitis B vaccine.
Since the licensing of the diphtheria, tetanus, whole-cell pertussis vaccine (DTwP) in
1948, its impact on childhood morbidity and mortality has decreased. Inclusion of DTwP
in childhood immunization programs continues to have wide acceptance in routine
immunization programs of infants and children throughout the world. However, the
nature of the pertussis antigens in DTP may influence the immunogenicity and
Effectiveness of the vaccine.
In the clinical development of the DTwP-HB-Hib vaccine, studies were conducted in
several countries to evaluate how incorporating Hib into a DTwP-HB tetravalent vaccine
might improve protection and kinetics. This Pentavalent vaccine proved to be highly
immunogenic for all vaccine antigens and no interference was demonstrated for any of
the antigens, including PRP/Hib. A very important, albeit unexpected, finding was



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that the kinetics response for the anti-HBs component was significantly improved in
some combination vaccines (17,18). The anti-HBs response reached a 95% seroprotection
level (³10mIU/ml) after the second dose of the DTwP-HB and DTwP-HB-Hib vaccines.
In contrast, when DTwP and HB were given separately, the seroprotection response level
for the anti-HBs component after the second dose of both vaccines was only 66%. The
Tetravalent DTwP-HB vaccine mixed with Hib also induced protective antibody titers
against diphtheria, tetanus, and H. influenzae, as well as high anti-pertussis titers. A study
conducted in five Latin American countries and involving 400 subjects confirmed the
immunogenicity and reactogenicity profile of the DTwP-HB-Hib Pentavalent vaccine
established earlier. (19)
There have been long-standing concerns about the relative safety of the whole-cell
pertussis component of this vaccine. The reactogenicity, temporally associated with the
wP component of the DTwP vaccine, including redness and swelling at the site of
injection, agitation, febrile seizures and hypotonic-hypo-responsive episodes, high fever,
persistent crying, and a fear of rare, but serious, acute or chronic neurological events, led
several countries to discontinue its inclusion in routine immunization programs and
prompted the development of a new generation of pertussis vaccines, the acellular (aP)
vaccines. It is important to mention that despite thorough investigations, the link
unexpected between wP vaccines and rare cases of permanent neurological damage has
not been confirmed . (9)
The average cost per person vaccinated and death averted up immunization coverage and
adding in DTP HB Hib in a Hypotetical Population of 1 million for 2001-2011 in (2001
US$, current vaccine prices) Latin America and the Caribbean:
Incremental discounted cost/person vaccinated           :       15.69
Incremental discounted deaths averted                   :       129
Incremental discounted cost/death averted               :       22,540
(Lorgan Brenzel et all, Vaccine-Preventable Diseases, Chapter 20,).
A randomized double-blind study from September 1998 to August 1999 to establish the
immunogenicity and reactogenicity of primary and booster vaccination of healthy
children with the new Pentavalent combined DTwP -HB/Hib given as a single injection,
compared with the reference regimen, the results indicated that the Pentavalent
combination vaccine provides an efficient and reliable way of implementing WHO
recommendations for controlling hepatitis B and Hib infections on a worldwide basis.
(Miquel Tregnaghi, Pio Lopez, Crisanta Rocha. Luis Rivera, Marie-Pierre David;
Ricardo Ruttimann, Lode Schuerman, A new DTPw-HB/Hib combination vaccine for
primary and booster vaccination of infants in Latin America, Revista Panamericana de
salud Publica vol.19 no.3 Wasnington Mar. 2006).


Thermostability of vaccines
Diphtheria and tetanus toxoids are some of the most stable vaccines in common use.
They are stable at temperatures of 2 to 8°C for years, at room temperature for months,
and at 37°C for weeks. At the temperature of 45°C the degradation of toxoids is
accelerated and their potency can decline during a few weeks. At 53°C toxoids lose
potency after few days, and at 60°C they lose potency after just a few hours. Freezing can


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reduce the potency of adsorbed toxoids, however, it does not seem to affect the
immunogenicity of unabsorbed products. The freezing point for adsorbed toxoids is
between -5°C and 10°C. Adsorbed toxoids should never be frozen.
In its usual presentation, DTP with thiomersal and aluminum adjuvant is susceptible to
freezing but relatively stable at 4°C for two years or more. It is resistant to storage for
several months at 22 to 25°C, for several weeks at 37°C, an-d for less than one week at
45°C. As with most protein-containing vaccines, temperatures higher than 56°C are
immediately deleterious.
These data suggest that HB vaccine is in the upper range of heat stability, together with
tetanus and diphtheria toxoids, among the vaccines commonly used in the immunization
programmes. The vaccine is stable for up to four years at temperatures of 2 to 8°C, for
months at 20°C to 25°C, for weeks at 37°C and for days at 45°C. As with other vaccines
adsorbed on aluminum salts, freezing of HB vaccine may cause a significant reduction of
potency. The freezing point of HB vaccine is about -0.5°C. The vaccine should always be
protected from being frozen, especially at the end of the cold chain when it is transported
in cold boxes and may come into close contact with cold packs.
The stability of conjugated polysaccharide vaccines, including Haemophilus influenzae
type b (Hib) vaccine, may depend on the impact of adverse factors on the strength of the
linkage between the polysaccharide and the protein carrier. Although there are few data
on these vaccines, preliminary results suggest that the lyophilized Hib vaccine (tetanus
toxoids conjugate vaccine containing purified polyribosyl-ribitolphosphate capsular
polysaccharide, PRP-T) is stable at refrigerator temperatures for 36 months and at 25°C
for at least 24 months. Reconstituted monovalent Hib vaccine or reconstituted Hib
vaccine combined with other vaccines (DTP, DTPHB, or DTP-IPV) should be destroyed
after an immunization session or within six hours. Liquid monovalent Hib or liquid Hib-
DTP vaccines are stable at refrigerator temperatures for 24 months. In multidose
formulation, liquid Hib and Hib-DTP vaccines may be used at a subsequent session, even
if they have been opened, according to the WHO Policy Statement on the use of opened
vials of vaccine in subsequent immunization sessions.

Population for application and conditions: Brazil
Brazil has highly successful National Immunization Days due to sustained use of social
mobilization; routine vaccination coverage has improved in the last years. Brazil is a
vaccine producing country, Biomanguinhos in Rio de Janeiro . The Immunological
Technology Institute (Bio-Manguinhos) is the technical-scientific unit of the Oswaldo
Cruz Foundation (Fiocruz), which produces and develops Immunological items to
respond to public health demands, currently the institute is the main immunobiological
provider to the Ministry of Health, supplying 47% o the vaccines demand under the PNI.
The National Immunization Program (PNI) establishes the regulations and strategies for
Immunological products use in Brazil. The program is coordinate by the National Health
Surveillance Agency (Anvisa), entity of the Ministry of Health in charge of national
vaccination action. In 2008 Brazil had 2.917.432 newborn (total population
191.480.630).
The production of combination vaccine have been licensed and introduced into the
immunization schedule of children in Brazil in 2009, including: diphtheria and tetanus


                                                                                          7
toxoids and whole pertussis vaccine DTwP-Haemophilus influenzae type b (Hib) vaccine
(DTwP-Hib); conjugate vaccine-hepatitis B vaccine, called Pentavalent DTP+HB+Hib, a
total 15,207 doses were applied by PNI.
Each dose of DTP+HB+Hib is given after 2 moths of birth to 11 months and at 29 days
of birth for newborn with Blood Dyscrasia, each dose of vaccine (0.5 ml) has:
    a.      Haemophilus influenzae type b (Hib): 10mg polysaccharide poluribosil-ribitol
            fosfato capsular purified (PRP) Haemophilusm influenzae type b (Hib)
    b.      DTP+HB: 30 UI absorbed toxoid diphtheriaewith less than 60 UI absorbed
            tetanus toxoid, with less than 4 UI of pertussis (coqueluche) and 10
            micrograms HbsAg recombinant
    c.      Inject able suspension. Adjuvant: Aluminum base.
Immunization in 3 doses, 2, 4 and 6 moths old, with intervals between doses for 60
days but can be at less interval of 30 days, apply subcutaneous. Subcutaneous injections
are administered at a 45-degree angle usually into the thigh for infants aged <12 months
and in the upper-outer triceps area of persons aged >12 months. Subcutaneous injections
can be administered into the upper-outer triceps area of an infant, if necessary. A 5/8-
inch, 23 to 25-gauge needle should be inserted into the subcutaneous tissue
(http://portal.saude.gov.br/portal/arquivos/pdf/indicacoes_cries.pdf).
The vaccine content polyribosylribitol phosphate (PRP) a human monoclonal antibody
reactive use in Hib as antibody for the capsule of H. Influenzae type b.

Diseases conditions

Diphtheria in Brazil keep reducing the cases 9 reporting cases in 2006, the tendency of
incidence and mortality in all group of ages, lethality has increase from 11% to 22%
related to decrease in number of cases for late diagnostic, deficiency in assistance or
access to health services prior to diagnostic. (Tabeta de casos confirmados de difteria,
Brazil e Grandes Reioes, 1997-2006).
Tetanus Neonatal in Brazil in the last 5 years 60 cases (12 cases per year) at 6 days of
live produce by contaminants like needles, non-sterilization. More in the North and North
East part of the country is related to delivery attention or woman vaccination between 12-
49 years. (Tabeta de casos confirmados de tetano, Brazil e Grandes Reioes, 1990-2007).
Pertussis in Brazil reported in 2006, cases 797 more in the North- East, incidence
mortality and lethality has been decreased because of pre scholar immunization. (Tabeta
de casos confirmados de coqueluche, Brazil e Grandes Reioes, 1991-2006).
Hepatitis B in Brazil reported in 2006, cases 5,124 transmission sexual, parenteral and at
the delivery time or after in 70-90% for AgHBe positive and 10-20% AgHBe negative,
deaths in 2007, cases 435. ( Secretaria de Vigilancia em Saude do Ministerio da Saude).




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Proposal using DSJI-PATH jet injector for intradermal use and
Biomanguinhos combination vaccine pentavalent DTP+HB+Hib

Purpose
This can be a Pilot study (Phase I) of safety randomized, observer-blinded follow by
Phase II safety and non-inferiority to determine whether immune responses suggesting
protection with conjugate subcutaneous vaccine DTP+HB+Hib (Biomanguinhos) can be
safely be induced in children s 2, 4 and 6 months old administered at three reduce doses
(0.1-0.15-0.2-0.25 mL?) sixty days intervals by the intradermal (ID) route with an
investigational ID spacer needle-free jet injector (JI), compared to standard subcutaneous
0.5 mL doses by needle-syringe (N-S) in this age group.

Objectives

   1.      Demonstrate the utility of jet injector in the delivery of vaccine with
           immunology purpose in the intradermal space in an efficient matter in
           quantity desirable controlled using bloodless free pathogens disposable
           cartridges and free cross contamination procedures.
   2.      The jet injector will deliver in the intradermal space the vaccine with
           minimum discomfort or damage to the skin and surrounding tissues.
   3.      The vaccination doses intradermal delivered by jet injector are in reduced
           amount comparing with the subcutaneous delivered needle and syringe use,
           decreasing over all cost, increasing potential coverage/vials, reducing
           procedure time.
   4.      The presence of immune response (seroconversion) with intradermal
           vaccination each dose at considerably smaller than the standard subcutaneous
           dose.

Primary Outcome Measures:

   1.      Vaccine intradermal delivery into dermis space and amount delivered.
   2.      Bloodless disposable cartridge evaluation.
   3.       Discomfort at the delivery time of vaccine.
   4.      Skin changes in the vaccination area during the time of the study.
   5.      Number of dose compare by dose/vial
   6.      Number of subjects with Anti-hepatitis B (HB) antibody concentrations above
           the cutt-off before (pre) and two months after 1st dose in ID and SC group
   7.      Number of subjects with Anti-polyribosyl-ribitol-phosphate (PRP) antibodies
           concentrations above the cutt-off before (pre) and two months after 1st dose in
           ID and SC group.
   8.      Number of subjects with Anti-diphtheria and Anti-tetanus antibodies
           concentrations above the cutt-off before (pre) and two months after 1st dose in
           ID and SC group




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   9.      Number of subjects with Anti-Bordetella pertussis (anti-Bp) antibody
           concentrations above the cutt-off before (pre) and two months after 1st dose in
           ID and SC group.

Secondary Outcomes Measures:
   1.      Number of subjects with Anti-hepatitis B (HB) antibody concentrations above
           the cutt-off two months after 2nd and 3rd dose in ID and SC group
   2.      Number of subjects with Anti-polyribosyl-ribitol-phosphate (PRP) antibodies
           concentrations above the cutt-off two months after 2nd and 3rd dose in ID and
           SC group.
   3.      Number of subjects with Anti-diphtheria and Anti-tetanus antibodies
           concentrations above the cutt-off two months after 2nd and 3rd dose in ID and
           SC group
   4.      Number of subjects with Anti-Bordetella pertussis (anti-Bp) antibody
           concentrations above the cutt-off two months after 2nd and 3rd dose in ID and
           SC group.
   5.      Number of subjects reporting discomfort at the delivery time of vaccination,
           2, 4 and 6 months in ID and SC groups
   6.      Number of subjects reporting skin changes in vaccination area at 2,4 and 6
           months in ID and SC groups
   7.      Numbers of mL used for vaccination on 2,4 and 6months in ID and SC
           groups.
   8.      Number of subjects reporting solicited symptoms within 4 days in post
           vaccination period at 2,4 and 6 months.
   9.      Number of subjects reporting unsolicited Adverse Events (AE) within the
           sixty days post vaccination period.
   10.     Number of subjects reporting Serious Adverse Events (SAE) within the sixty
           days post vaccination period.
   11.     Geometric mean titers (GMT) two months after each doses for ID and SC
           groups.


Vaccines

All vaccines will be manufactured by Immunological Technology Institute (Bio-
Manguinhos) the DTP+HB+Hib


Serology

Blood samples (3ml) for serology assessment, can be taken prior to the first dose, two
months after 1st dose, two months after 2nd dose and one month after 3rd dose, sera can be
store at –20 C until analyses are performed Standard Operational Procedures (SOP’s) can
be in place for time points collections, identification, and storage tracking.



                                                                                        10
Measure antibodies against hepatitis B surface antigen (anti-HBs) can be use a radio
immunoassay (AUSUB Abbott Laboratory) the assay cut off at 10 mIU/mL.
Anti-tetanus and anti-diphtheria antibody concentrations can be measure by ELISA, with
cutoff of 0.1 IU/ml.
Anti-PRP antibody concentrations can be measure by enzyme-linked immunosorbent
assay (ELISA) with cutoff of 0.15 micrograms/mL.
Anti-Bordetella pertussis (anti-Bp) antibody concentration can by measure using ELISA
kit with cutoff 0f 15 ELISA units/mL (EU/mL).
With the exception of anti-Bp, antibody concentrations at or above the assay cutoffs can
be considered to be indicative of protection against disease.


Reactogenicity

Details of adverse events in diary cards can be during 4 days follow –up period after each
vaccination. Local symptoms include pain, redness and swelling at the site of injection
and solicited general symptoms like drowsiness, fever (>37.5 C or > 40.5 C), fussiness or
irritability, and loss appetite, inconsolable crying for more than 3 hours within 48 hours
of vaccination, hypotonic-hyporesponsive episode, seizure with or without fever-the child
would be excluded from further vaccination dosing as a precautionary measure as those
events might be attributed to the whole cell B pertussis component Intensity of general
symptoms (apart from fever) can be grade in point scale. All other symptoms can be
recorded for a period up to 30 days post vaccination, and serious adverse events (SAEs)
recorded during the entire study period.


Statistical analysis

The statistical analysis can be performed for the according –to-study cohorts.
Seropositivity/seroprotection/vaccine response rates and geometric mean antibody
concentrations (GMCs) can be calculated with 95% confidence intervals (CIs) at each
blood sampling time point.
The incidence of solicited symptoms can be calculated with exact 95% CIs for each type
of adverse event
The difference between groups with respect to Seropositivity/seroprotection/vaccine
response rates following primary vaccination can be calculated with 90% CIs. The 90%
CIs can be computed to demonstrate noninferiority, ensuring a 5% type I error when
comparing the upper limit to the predefined non-inferiority limit (one sided test). The
response following primary vaccination with the intradermal candidate can be considered
to be non-inferior to that observed with the subcutaneous vaccines if the upper limit of
the 90% CI of the group difference can be <5% for anti-PRP >0.15 microgram /mL and
<10% for all others antigens.
The FDA and EMEA accepted method to show non inferiority of two administration
delivery system to agree a priory on a clinically acceptably difference between the two
systems, and then build 90% confidence limits around that difference.



                                                                                       11
References
 1. Janeway CA Jr, Travers P, Walport M, Capra JD. Immunobiology: the immune
     system in health and disease. 4th ed. New York: Garland Publishing, 1999.
 2. Payler DK, Skirrow MB. Intradermal influenza vaccination. Br Med J
     1974;2:727-727. [Free Full Text]
 3. Tauraso NM, Gleckman R, Pedreira FA, Sabbaj J, Yahwak R, Madoff MA. Effect
     of dosage and route of inoculation upon antigenicity of inactivated influenza virus
     vaccine (Hong Kong strain) in man. Bull World Health Organ 1969;41:507-
     516. [Web of Science][Medline]
 4. Sabchareon A, Chantavanich P, Pasuralertsakul S, et al. Persistence of antibodies
     in children after intradermal or intramuscular administration of preexposure
     primary and booster immunizations with purified Vero cell rabies vaccine. Pediatr
     Infect Dis J 1998;17:1001-1007. [CrossRef][Web of Science][Medline]
 5. Redfield RR, Innis BR, Scott RM, Cannon HG, Bancroft WH. Clinical evaluation
     of low-dose intradermally administered hepatitis B virus vaccine: a cost reduction
     strategy. JAMA 1985;254:3203-3206. [Free Full Text]
 6. Donald R Graham, Bruce B Dan, Pamela Bertagnoll, Richard E Dixon Am J
     Public Health 1981;71:1040-1043
 7. Hingson RA, Davis HS, Rosen M. Historical development of jet injection and
     envisioned uses in mass immunization and mass therapy based upon two decades'
     experience. Mil Med 1963;128:516--24.
 8. Reis EC, Jacobson RM, Tarbell S, Weniger BG. Taking the sting out of shots:
     control of vaccination-associated pain and adverse reactions. Pediatr Ann 1998
     Jun;27(6):375-86.
 9. Occupational Safety and Health Administration. Occupational exposure to
     bloodborne pathogens; needlestick and other sharps injuries; final rule (29 CFR
     Part 1910). Federal Register 2001;66:5318--25. Available at http://www.osha-
     slc.gov/FedReg_osha_pdf/FED20010118A.pdf.
 10. Simonsen L, Kane A, Lloyd J, Zaffran M, Kane M. Unsafe injections in the
     developing world and transmission of bloodborne pathogens: a review. Bull
     World Health Organ 1999;77(10):789-800.
 11. . Kane A, Lloyd J, Zaffran M, Simonsen L, Kane M. Transmission of hepatitis B,
     hepatitis C and human immunodeficiency viruses through unsafe injections in the
     developing world: model-based regional estimates. Bull World Health Organ
     1999;77(10):801-7.
 12. . CDC. Needle-free injection technology. Atlanta, GA: US Department of Health
     and Human Services, CDC, National Immunization Program, 2001. Available at
     <www.cdc.gov/nip/dev/jetinject.htm. Accessed November 8, 2001.
 13. CDC. Hepatitis B associated with jet gun injection---California [Epidemiologic
     notes and reports]. MMWR Jun 13, 1986 / 35(23);373-6.
 14. Canter J, Mackey K, Good LS, et al. Outbreak of hepatitis B associated with jet
     injections in a weight reduction clinic. Arch Intern Med 1990 Sep;150(9):1923-7.


                                                                                     12
15. . Brito GS, Chen RT, Stefano IC, Campos AM, Oselka G. Risk of transmission of
    HIV and other blood-born diseases via jet injectors during immunization mass
    campaigns in Brazil [Abstract PC0132]. 10th International Conference on AIDS,
    Yokohama, 7--12 August 1994;10:301. Available
    at http://www.aegis.com/pubs/aidsline/1994/dec/m94c3258.html. Accessed
    November 8, 2001.
16. Hoffman PN, Abuknesha RA, Andrews NJ, Samuel D, Lloyd JS. Model to assess
    the infection potential of jet injectors used in mass immunization. Vaccine 2001
    Jul 16;19(28-29):4020-7.
17. Decker MD, Edwards KM, Bogaerts HH. Combination vaccines. In: Plotkin
    SA,Orenstein WA, eds. Vaccines. 4th ed. Philadelphia: WB Saunders, 2004;825–
    861.
18. Faingezicht I, Avila-Aguerro ML, Cervantes Y, Fourneau M, Costa Clemens SA.
    Primary and booster vaccination with DTPw-HB/Hib pentavalent vaccine in
    Costa Rican children who had received a birth dose of hepatitis B vaccine. Rev
    Panam Salud Publica 2002;12(4):247–257.
19. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, et al.
    Ileal-lymphoid nodular hyperplasia, non-specific colitis, and pervasive
    developmental disorder in children. Lancet 1998;351(9103):637–641.




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