Challenges in vaccine access and delivery for developing nations

What is the impact of the Pertussis vaccine in the prevention and control of whooping cough?

Pertussis is an important death cause among infants worldwide, and continues to constitute a public health problem even in countries with elevated vaccination coverage. In 2008, World Health Organization (WHO) reported 16 million cases out of which 95% corresponded to developing countries. Approximately, 195 000 infants died as a result of this disease.

The causal agent of the whooping cough is the bacterium Bordetella pertussis which is transmitted by saliva particles containing bacteria. Clinical manifestations depend greatly on age and immunization status of the host. The incubation period lasts about 10 days; the clinical evolution of the disease usually takes 4-6 weeks and is divided in three stages: catarrhal, paroxysmal, and convalescent stage. The most frequent complication is pneumonia.

Pertussis is an endemic disease in many parts of the world. Pertussis prevalence before vaccination against this disease was very high with cyclic patterns peaking every 2 to 5 years. Although today the prevalence of this disease has decreased, the cyclic patterns are still repeated.

See Figure 1 showing pertussis cases reported annually as well as vaccination coverage with DPT3.

Which vaccine is key to the prevention and control of whooping cough?

At the beginning of the past century, this disease caused high morbidity and mortality affecting mostly children under 5 years of age. In response, during the mid-twentieth century, the complete cell pertussis vaccine was introduced; the result was a significant reduction in the number of cases reported worldwide.

However, in 1974, Kulenkampff et al. observed that the pertussis component of the DPT vaccine with whole cell pertussis was related with neurological damage to children vaccinated between 1961 and 1972. Later, Steward reported the same situation in 1977.

Once the relation between the DPT vaccine (in particular the pertussis whole component of it) and important neurological damage was established, it became necessary to determine whether this effect was due to the vaccine itself or its quality. In 1978, Griffith determined that the quality, safety, and efficacy of the vaccines applied and investigated during the 1964 to mid-1977 period, depended upon diverse factors: i) the strain selection of Bordetella pertussis used in the production of vaccines, ii) the technology used in the production of the vaccine, and iii) the quality control tests used to evaluate the vaccine. Also, it was observed that the potency of the vaccines displayed great variability. At the time, the accepted specification was 4 PU (Potency Units) per dose. In some batches, though, a lower potency was observed and thus they did not provide adequate protection. In such cases, an adjuvant was added to the vaccine to enhance the potency.

The antecedent of adverse reactions to the existing vaccine made it necessary to produce vaccines with less reactogenicity but providing equal or enhanced immunological protection in humans.

This lead to the production of acellular pertussis vaccines, which are composed of purified proteins from B. pertussis. These vaccines are formulated with two to six different components of which the pertussis toxin and detoxified filamentous haemagglutinin are always included. With the advent of the acellular pertussis vaccine there has been a reduction in the number of adverse reactions. Therefore, many developed countries have replaced the whole cell vaccine by that of the acellular type for their vaccination programs.

Which type of Pertussis vaccine is most commonly used to prevent and control whooping cough, and what are its key features?

For several decades, programs using pertussis vaccines of documented quality to immunize infants have been highly successful in preventing severe pertussis in infants worldwide. Two types of pertussis vaccines are available: whole-cell (wP) vaccines based on killed B. pertussis organisms, and acellular (aP) vaccines based on highly purified, selected components of this agent. Different manufacturers use different strains of B. pertussis, and the “genealogy” of these bacterial sources is not readily available. In addition, significant heterogeneity across studies complicates comparisons of the efficacy and effectiveness of different vaccines. Both vaccines are considered to provide effective protection against the disease. Below you will find a brief description of these vaccines.

Available vaccines and their features, efficacy and safety.

There are two types of pertussis vaccines: 1) whole-cell (wP) vaccines based on killed B. pertussis organisms, and 2) acellular (aP) vaccines based on highly purified, selected components of this agent.

The duration of immunity has been observed to vary. In the case of the whole-cell vaccine, it has been estimated that an individual is protected from 6 to 9 years (4-12) after the vaccination. The acellular vaccine confers protection estimated in 5 to 6 years.

Adverse effects have been reported after the administration of both vaccines; of whole cell vaccine and acelular vaccine. The magnitude of the adverse events include from local reactions to hypersensibility and convulsions. Some authors suggest that acellular type vaccines produce less adverse events, but this has not been settled and the debate is ongoing.

See Table I for characteristics of whole cell vs. acellular pertussis vaccine. See Table II for vaccine recommendations.

Available vaccines, dosing information for prevention, and adverse reactions.

Cost

Regarding cost, the whole cell vaccine is clearly cheaper. WHO estimated a cost increase due to the introduction of the acellular vaccine from US$0.15 to US$8.15 clearly reflecting a much higher cost for the acellular type vaccine. In 2007, Pan American Health Organization (PAHO) concluded there is no reason to substitute the whole cell vaccine with the acellular vaccine considering a cost effectiveness analysis.

Adverse Effects (AE) associated to the vaccine

Adverse effects have been reported after the application of both vaccine types; whole cell and acellular. The magnitude of the events ranges from local reactions to hypersensibility and convulsions.

Some authors suggest that acellular type vaccines produce less adverse reactions, but this has not been settled and the debate is ongoing. Also, studies to ascertain the frequency of severe and rare reactions are being carried out. Apart from the AE analysis for both vaccine types, AE analysis have been conducted to study the combination of both vaccine types in a single schedule. These analyses have found differences in the prevalence of adverse effects in the application of combined schedules.

A high percentage (40-80%) of people given whole cell DPT display minor local reactions such as pain, numbness, edema, and erythema. Other events related to this vaccine are fever (over 38°C), agitation, loss of appetite (20% to 35%), drowsiness (33% to 62%), and in a lesser proportion vomiting (6% a 13%), continued crying and convulsions are less common (under 1%), and hypotonic hyporreactive episodes are rare (less than one case in every 1000 to 2000 vaccinations). Severe adverse effects can include cerebral damage and encephalopathy although there is no sufficient evidence to uphold this information according to reports from Advisory Committee on Immunization Practices (ACIP) of the USA and WHO. Moreover, WHO rejects a causal relation between DPT vaccine and autism, infantile spasms, Reye syndrome, and Sudden Infant Death Syndrome.

Decker et al. report the same adverse effects for the acellular vaccine as those caused by the whole cell vaccine but in lesser degree. Besides, independently of the number of components present in the vaccine, the frequency of adverse reactions after the first dose of acellular vaccines did not differ from that observed in the group that was given a placebo or after a shot of only DT toxoids.

After a booster shot (fourth dose) with acellular pertussis vaccine was given to children previously vaccinated with a whole cell vaccine, milder adverse effects have been reported than when the booster was given to children who had previously received an acellular vaccine.

Local reactions tend to increase with age and the number of injections; therefore, the use of whole cell vaccines to immunize teenagers and adults is not recommended. As a result, acellular vaccines with a reduced antigen concentration have been formulated to the end of reducing the reactogenicity.

Vaccines in development.

Whole Cell Pertussis Vaccine:

Vaccines containing whole pertussis cells as a component have been widely used as part of the combined DPT vaccine together with the tetanus toxoid and diphtheria toxoid for decades. In spite of its reactogenicity and the occurrence of adverse effects after immunization, this type of vaccine continues to be produced throughout the world due to its effectiveness in the prevention of pertussis. That is why WHO still recommends its inclusion in national immunization programs independently of the emergence of acellular vaccines which are less reactogenic.

According to the guidelines issued by WHO, a whole cell vaccine is a suspension of dead cells of one or more strains of Bordetella pertussis, which are to be adequately treated so as to minimize their toxicity and preserve their potency. These vaccines must meet the following recommendations:

Production recommendations:

Vaccine potency by vial: 46 UI
Opacity: 10 UI
To determine the serotype of the strains of B. pertussis monoclonal antibodies anti-fimbriae monoclonal antibodies serotypes 2 and 3 are used.
The activity of the pertussis toxin must be 10 000 UI, which is used to determine the residual toxin in the vaccine.

Acellular pertussis vaccine:

The first acellular vaccine was developed in Japan in 1981. There are different types of vaccines depending upon the antigens composition, the bacterial strain used in the production of the primary antigen, the production and detoxification methods, the adjuvants used, and the use of preservatives such as thiomersal. Currently, there is no consensus as to what the ideal antigenic composition of the acellular pertussis vaccine should be.

Current acellular vaccines from different manufacturers must be treated as distinct and unique products, since they include one or more different components at different concentrations. In addition, they present different adsorption rates of the adjuvants used. It is also important to highlight the fact that the origin of the individual antigens (the different strains of B. pertussis) and the purification methods used have an impact on the product.

Taking this into consideration, it is very complicated to compare the protective efficacy in humans of the different acellular vaccines if this comparison is made using a single laboratory test.

It is of the utmost importance to carefully consider any alteration in the production or formulation of an acellular vaccine that has been proven to be safe and effective in clinical trials.

Summary of current controversies.

Whole cell versus acellular pertussis vaccine

Several questions arise time and again about these vaccines: What is the difference between these vaccines? Is it possible to entirely phase out the whole cell pertussis vaccine? Is it important to continue the application of the whole cell vaccine?

The whole cell vaccine was used for many years for the prevention and control of pertussis worldwide. It is still applied in some countries, mostly as part of vaccination programs in developing countries. The initial vaccination schedule consists of four initial doses during infancy (2, 4, 6, and 18 months of age) and reinforcement in pre-school age. Its use has been declining due to the adverse effects it produces which range from local pain to convulsions and death in the worst case.

Regarding the production of the whole-cell pertussis vaccine, we can mention that the manufacturing procedures have undergone important modifications. The result of these modifications has been a change in the immune response (mostly in the antibody titers) which has resulted in greater efficacy.

Regarding quality control tests of the whole cell pertussis vaccine, it has been observed that the method to determine the potency of the vaccine (the Hendrick test) shows important variations, this is due to the use of an animal model for the test. So far, there is no substitute for this test has been found. Furthermore, one of the most frequent problems with the whole cell pertussis vaccine is the toxicity determination due to the great variability in the results of quality control methods used.

Was the old pertussis vaccine safe? The old pertussis vaccine was called the “whole-cell” vaccine and had a high rate of severe side effects. Persistent, inconsolable crying occurred in one of every 100 doses, fever greater than 105 degrees occurred in one of every 330 doses, and seizures with fever occurred in one of every 1,750 doses. Due to negative publicity about this vaccine, the use of pertussis vaccine decreased in many areas of the world. For example, the Japanese Ministry of Health decided to stop using the pertussis vaccine in 1975. In the three years before the vaccine was discontinued, there were 400 cases of pertussis and 10 deaths from pertussis in Japan. In the three years after the pertussis vaccine was discontinued, there were 13,000 cases of pertussis and 113 deaths! It should be noted that although the side effects of the pertussis vaccine were “high”, children didn’t die from pertussis vaccine, they died from pertussis infection. The Japanese Ministry of Health, realizing how costly their error had been, soon reinstituted the use of pertussis vaccine. The children of Japan proved that the benefits of the old pertussis vaccine clearly outweighed the risks.

During the period comprised between 1998 and 2001, a study to determine the affectivity of the pertussis vaccine in children aged 6 to 59 months was conducted in the United States.

The vaccines included in this study were: whole cell vaccine and two acellular type vaccines; one of two components and the other of four components. The conclusion reached was that the affectivity of the vaccines is greater when combined vaccination (whole cell and acellular type vaccines) is used as opposed to using a single type of vaccine.

In Canada, from 1991 to 2004, a study conducted in hospitals evaluated the effect on children under the age of 5 of changing the pertussis vaccine from the whole cell type to the acellular type. The authors concluded that there was a decrease in the number of hospitalizations related to pertussis in children between 4 and 59 months of age when the acellular type pertussis vaccine had been applied and that the affectivity of the vaccine was consistent with the protection provided. In contrast, the group who received the whole cell pertussis vaccine had an increase in the number of hospitalizations in children under the age of two months.

As seen so far, the acellular pertussis vaccine is better than the whole cell vaccine; however, it is important to take into consideration the immunity produced by each vaccine since the induced response produced by each type is different.

Riebernikolaus et. al. point out the differences between the immune responses, both cellular and humoral, after an acellular pertussis booster was given to teenagers following a base of whole-cell pertussis vaccine in a combined schedule of whole and acellular pertussis vaccines. The whole cell vaccine displays a response based on a cytosine model associated to Th1 cells which displays a greater effect on the proliferation of specific T cells; whereas the acellular pertussis vaccine shows a model of cytosine associated to Th2 cells with higher antibody titers in the humoral response.

The results of this study show that the immune response is better when there is a combined vaccination schedule. That is, one including a starter vaccine of the whole-cell type followed by a booster of the acellular type since B. pertussis contains molecules such as lipopolysaccharides which contribute to the production of long term memory B plasma cells, and promote an enhanced and faster immune response.

Are there specific guidelines for the use of some of these vaccines?

National recommendations vary considerably, and different schedules are used for the primary series, such as: immunization at the ages of 6, 10 and 14 weeks; at 2 months, 3 months and 4 months; at 3 months, 4 months and 5 months; and at 2 months, 4 months and 6 months. A number of countries administer the vaccine at 3 months, 5 months and 12 months: the doses at 3 months and 5 months may be considered the primary series and the dose at 12 months a booster. In principle, the same type of wP-containing or aP-containing vaccines should be given throughout the primary course of vaccination. However, the limited data available do not suggest that changing between an aP-containing and a wP-containing vaccine interferes with safety or immunogenicity. Therefore, if the previous type of vaccine is unknown or unavailable, any wP vaccine or aP vaccine may be used for subsequent doses.

References

Black, RE, Cousens, S, Johnson, HL. “Global, regional, and national causes of child mortality in 2008: a systematic analysis”. Lancet. vol. 375. 2010. pp. 1969-19874.

“Vaccine Preventable Disease Surveillance: Overview”. World Health Organization. 2011.

Kulenkampff, M, Schwartzman, JS, Wilson,, J. “Neurological complications of pertussis inoculation”. Arch Dis Child. vol. 49. 1974. pp. 46-49.

“Recommendations for whole-cell pertussis vaccines”. Technical Report Series No. 941 2007.

“Requirements for diphtheria, tetanus, pertussis and combined vaccines”. Technical Report Series No. 800 1990.

Edwards, KM, Decker, MD, Plotkin, SA, Orenstein, WA, Offit, PA. “Pertussis vaccine”. Vaccines. 2008. pp. 467-518.

Rieber, N, Graf, A, Belohradsky, BH. “Differences of humoral and cellular immune reponse to an acellular pertussis booster in adolescents with a whole cell or acellular primary vaccination”. Vaccine. vol. 26. 2008. pp. 6929-6935.

Gustafsson, L, Hallander, OH, Olin, Pm. “A Controlled trial of two-component acellular, a five-component acellular, and whole-cell pertussis vaccine”. NEJM. vol. 334. 1996. pp. 349-355.

Decker, MD, Edwards, KM, Steinhoff,, MC. “Comparison of 13 Acellular Pertussis Vaccines: Adverse Reaction”. Pediatrics. vol. 96. 1995;. pp. 557-566.

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