T. Jacob John

Herd immunity and herd effect: new insights and definitions.

The term herd immunity has been used by various authors to conform to different definitions. Earlier this situation had been identified but not corrected. We propose that it should have precise meaning for which purpose a new definition is offered: “the proportion of subjects with immunity in a given population”. This definition dissociates herd immunity from the indirect protection observed in the unimmunised segment of a population in which a large proportion is immunised, for which the term ‘herd effect’ is proposed. It is defined as: “the reduction of infection or disease in the unimmunised segment as a result of immunising a proportion of the population”. Herd immunity can be measured by testing a sample of the population for the presence of the chosen immune parameter. Herd effect can be measured by quantifying the decline in incidence in the unimmunised segment of a population in which an immunisation programme is instituted. Herd immunity applies to immunisation or infection, human to human transmitted or otherwise. On the other hand, herd effect applies to immunisation or other health interventions which reduce the probability of transmission, confined to infections transmitted human to human, directly or via vector. The induced herd immunity of a given vaccine exhibits geographic variation as it depends upon coverage and efficacy of the vaccine, both of which can vary geographically. Herd effect is determined by herd immunity as well as the force of transmission of the corresponding infection. Clear understanding of these phenomena and their relationships will help improve the design of effective and efficient immunisation programmes aimed at control, elimination or eradication of vaccine preventable infectious diseases.

EVALUATION OF SIMPLE CLINICAL SIGNS FOR THE DIAGNOSIS OF ACUTE LOWER RESPIRATORY TRACT INFECTION

The reliability of clinical signs that might be used by village health workers in distinguishing acute lower respiratory infection (LRI) from upper respiratory infections (URI) in children was evaluated. 142 infants and 108 preschool children with LRI and 151 infants and 281 preschool children with URI, attending hospital, were studied. Respiratory rates of over 50/min in infants and over 40/min in children 12-35 months of age, as well as a history of rapid breathing and the presence of chest retractions in both age groups, were found to be sensitive and specific indicators of LRI. Increased respiratory rates and history of rapid breathing were also sensitive in diagnosis of less severe LRI that did not necessitate admission to the wards, whereas chest retraction was not. All these clinical signs had a low sensitivity in diagnosing LRI in children aged 36 months and over.

Immunogenicity of bivalent types 1 and 3 oral poliovirus vaccine: a randomised, double-blind, controlled trial

BACKGROUND Poliovirus types 1 and 3 co-circulate in poliomyelitis-endemic countries. We aimed to assess the immunogenicity of a novel bivalent types 1 and 3 oral poliovirus vaccine (bOPV). METHODS We did a randomised, double-blind, controlled trial to assess the superiority of monovalent type 2 OPV (mOPV2), mOPV3, or bOPV over trivalent OPV (tOPV), and the non-inferiority of bivalent vaccine compared with mOPV1 and mOPV3. The study was done at three centres in India between Aug 6, 2008, and Dec 26, 2008. Random allocation was done by permuted blocks of ten. The primary outcome was seroconversion after one monovalent or bivalent vaccine dose compared with a dose of trivalent vaccine at birth. The secondary endpoints were seroconversion after two vaccine doses compared with after two trivalent vaccine doses and cumulative two-dose seroconversion. Parents or guardians and study investigators were masked to treatment allocation. Because of multiple comparisons, we defined p≤0·01 as statistically significant. This trial is registered with Current Controlled Trials, ISRCTN 64725429. RESULTS 900 newborn babies were randomly assigned to one of five vaccine groups (about 180 patients per group); of these 70 (8%) discontinued, leaving 830 (92%) for analysis. After the first dose, seroconversion to poliovirus type 1 was 20% for both mOPV1 (33 of 168) and bOPV (32 of 159) compared with 15% for tOPV (25 of 168; p>0·01), to poliovirus type 2 was 21% (35 of 170) for mOPV2 compared with 25% (42 of 168) for tOPV (p>0·01), and to poliovirus type 3 was 12% (20 of 165) for mOPV3 and 7% (11 of 159) for bOPV compared with 4% (7 of 168) for tOPV (mOPV3 vs tOPV p=0·01; bOPV vs tOPV; p>0·01). Cumulative two-dose seroconversion to poliovirus type 1 was 90% (151 of 168) for mOPV1 and 86% (136 of 159) for bOPV compared with 63% (106 of 168) for tOPV (p<0·0001), to poliovirus type 2 was 90% (153 of 170) for mOPV2 compared with 91% (153 of 168) for tOPV (p>0·01), and to poliovirus type 3 was 84% (138 of 165) for mOPV3 and 74% (117 of 159) for bOPV compared with 52% (87 of 168) for tOPV (p<0·0001). The vaccines were well tolerated. 19 serious adverse events occurred, including one death; however, these events were not attributed to the trial interventions. INTERPRETATION The findings show the superiority of bOPV compared with tOPV, and the non-inferiority of bOPV compared with mOPV1 and mOPV3. FUNDING GAVI Alliance, World Health Organization, and Panacea Biotec.

Continuing challenge of infectious diseases in India

In India, the range and burden of infectious diseases are enormous. The administrative responsibilities of the health system are shared between the central (federal) and state governments. Control of diseases and outbreaks is the responsibility of the central Ministry of Health, which lacks a formal public health department for this purpose. Tuberculosis, malaria, filariasis, visceral leishmaniasis, leprosy, HIV infection, and childhood cluster of vaccine-preventable diseases are given priority for control through centrally managed vertical programmes. Control of HIV infection and leprosy, but not of tuberculosis, seems to be on track. Early success of malaria control was not sustained, and visceral leishmaniasis prevalence has increased. Inadequate containment of the vector has resulted in recurrent outbreaks of dengue fever and re-emergence of Chikungunya virus disease and typhus fever. Other infectious diseases caused by faecally transmitted pathogens (enteric fevers, cholera, hepatitis A and E viruses) and zoonoses (rabies, leptospirosis, anthrax) are not in the process of being systematically controlled. Big gaps in the surveillance and response system for infectious diseases need to be addressed. Replication of the model of vertical single-disease control for all infectious diseases will not be efficient or viable. India needs to rethink and revise its health policy to broaden the agenda of disease control. A comprehensive review and redesign of the health system is needed urgently to ensure equity and quality in health care. We recommend the creation of a functional public health infrastructure that is shared between central and state governments, with professional leadership and a formally trained public health cadre of personnel who manage an integrated control mechanism of diseases in districts that includes infectious and non-infectious diseases, and injuries.

Immunogenicity of supplemental doses of poliovirus vaccine for children aged 6-9 months in Moradabad, India: a community-based, randomised controlled trial

BACKGROUND The continued presence of polio in northern India poses challenges to the interruption of wild poliovirus transmission and the management of poliovirus risks in the post-eradication era. We aimed to assess the current immunity profile after routine doses of trivalent oral poliovirus vaccine (OPV) and numerous supplemental doses of type-1 monovalent OPV (mOPV1), and compared the effect of five vaccine formulations and dosages on residual immunity gaps. METHODS We did a community-based, randomised controlled trial of healthy infants aged 6-9 months at ten sites in Moradabad, India. Serum neutralising antibody was measured before infants were randomly assigned to a study group and given standard-potency or higher-potency mOPV1, intradermal fractional-dose inactivated poliovirus vaccine (IPV, GlaxoSmithKline), or intramuscular full-dose IPV from two different manufacturers (GlaxoSmithKline or Panacea). Follow-up sera were taken at days 7 and 28. Our primary endpoint was an increase of more than four times in antibody titres. We did analyses by per-protocol in children with a blood sample available before, and 28 days after, receiving study vaccine (or who completed study procedures). This trial is registered with Current Controlled Trials, number ISRCTN90744784. FINDINGS Of 1002 children enrolled, 869 (87%) completed study procedures (ie, blood sample available at day 0 and day 28). At baseline, 862 (99%), 625 (72%), and 418 (48%) had detectable antibodies to poliovirus types 1, 2, and 3, respectively. In children who were type-1 seropositive, an increase of more than four times in antibody titre was detected 28 days after they were given standard-potency mOPV1 (5/13 [38%]), higher-potency mOPV1 (6/21 [29%]), intradermal IPV (9/16 [56%]), GlaxoSmithKline intramuscular IPV (19/22 [86%]), and Panacea intramuscular IPV (11/13 [85%]). In those who were type-2 seronegative, 42 (100%) of 42 seroconverted after GlaxoSmithKline intramuscular IPV, and 24 (59%) of 41 after intradermal IPV (p<0·0001). 87 (90%) of 97 infants who were type-3 seronegative seroconverted after intramuscular IPV, and 21 (36%) of 49 after intradermal IPV (p<0·0001). INTERPRETATION Supplemental mOPV1 resulted in almost total seroprevalence against poliovirus type 1, which is consistent with recent absence of poliomyelitis cases; whereas seroprevalence against types 2 and 3 was expected for routine vaccination histories. The immunogenicity of IPV produced in India (Panacea) was similar to that of an internationally manufactured IPV (GSK). Intradermal IPV was less immunogenic.

Disease surveillance at district level: a model for developing countries

For over a decade we have maintained within a district of 5 million people, a system of prompt reporting of cases of childhood vaccine-preventable diseases, encephalitis, meningitis, hepatitis, and rabies; together with a sentinel laboratory surveillance of cholera, typhoid fever, malaria, HIV infection and antimicrobial-resistance patterns of selected pathogens. The system combined government and private sectors, with every hospital enrolled and participating. Reports were scanned daily on a computer for any clustering of cases. Interventions included investigations, immunisation, antimicrobial treatment, health education, and physical rehabilitation of children with paralysis. All vaccine-preventable diseases have declined markedly, whilst malaria and HIV infections have increased steadily. Annual expense was less than one US cent per head. The reasons for the success and sustainability of this model include simplicity or reporting procedure, low budget, private-sector participation, personal rapport with people in the network, regular feedback of information through a monthly bulletin, and the visible interventions consequent upon reporting. This district-level disease surveillance model is replicable in developing countries for evaluating polio eradication efforts, monitoring immunisation programmes, detecting outbreaks of old or new diseases, and for evaluating control measures.

A Global Perspective on Vaccine Safety and Public Health: The Global Advisory Committee on Vaccine Safety

Established in 1999, the Global Advisory Committee on Vaccine Safety advises the World Health Organization (WHO) on vaccine-related safety issues and enables WHO to respond promptly, efficiently, and with scientific rigor to issues of vaccine safety with potential global importance. The committee also assesses the implications of vaccine safety for practice worldwide and for WHO policies. We describe the principles on which the committee was established, its modus operandi, and the scope of the work undertaken, both present and future. We highlight its recent recommendations on major issues, including the purported link between the measles-mumps-rubella vaccine and autism and the safety of the mumps, influenza, yellow fever, BCG, and smallpox vaccines as well as that of thiomersal-containing vaccines.

Immune response of infants to fractional doses of intradermally administered inactivated poliovirus vaccine

Seventy eight infants aged 6-8 weeks received either two doses of 0.1 ml of inactivated poliovirus vaccine (IPV) intradermally 8 weeks apart (group A) or three doses 4 weeks apart (group B). Pre- and 4 weeks post-immunization serum samples were tested for the presence and titer of neutralizing antibody to poliovirus types 1, 2 and 3. The seroconversion rates to poliovirus types 1, 2 and 3 were 90, 70 and 97%, respectively, among infants in group A and 90, 80 and 98%, respectively, in group B; in children without pre-existing maternal antibody, seroconversion rates were 100% to all three poliovirus serotypes in both groups. These rates were comparable to those in children receiving five doses of OPV or two doses of intramuscular IPV. Intradermal administration of fractional doses of IPV may be a less expensive alternative for use in developing countries.

EPIDEMIC HEPATITIS B CAUSED BY COMMERCIAL HUMAN IMMUNOGLOBULIN

An epidemic of acute hepatitis B followed the administration of human immunoglobulin to members of the staff of a mission hospital in India and their families. Jaundice developed in 123 (38%) of 325 persons inoculated. Hepatitis-B surface antigen was detected in three of the batches of immunoglobulin which were available for testing.

Global safety of vaccines: strengthening systems for monitoring, management and the role of GACVS.

Vaccines have contributed enormously in reducing the impact of many infectious diseases, and the expanded use of new and existing vaccines provides unprecedented potential for further reducing the global burden of infectious diseases. Yet, as with the deployment of other technologies, their use may also sometimes be associated with undesirable effects that need to be identified rapidly, understood and minimized. In this article, we review the models and systems that have been developed to monitor and respond to concerns regarding vaccine safety and we give illustrative examples of real or perceived vaccine safety issues. The Global Advisory Committee on Vaccine Safety (GACVS) was set up 10 years ago and charged to provide the WHO with independent advice on vaccine safety issues. The role of the GACVS is both to analyze and to interpret reports of the adverse effects of vaccines that impact on global vaccination programs and strategies, and to foster the development of improved surveillance systems to detect any adverse effects of vaccines, particularly in low- and middle-income countries. It also monitors the development of new vaccines during clinical testing and advises on the safe use of vaccines in immunization programs. As success is achieved with reducing the burden of vaccine-preventable diseases, there will be increasing attention focused on potential adverse effects, on the development of effective surveillance systems to detect adverse effects, and on improved methods to manage and control any harmful consequences of vaccination.