Should there be a World Health Assembly resolution for malaria eradication? Opinion against.

A resolution for eradicating malaria, if passed by the World Health Assembly (WHA), will have a distracting effect on all countries with malaria. The continued prevalence of malaria is indicative of weak public health infrastructure. True, smallpox was eradicated by international efforts following WHA resolution: the success factor was primary prevention using a safe and effective vaccine. A resolution to eradicate polio was passed in 1988, with a target year of 2000, but even in 2019 success is not within reach. Public health experts are hesitant to move forward with measles eradication before polio is eradicated. Country by country elimination of malaria is a better way, ensuring the strengthening of public health infrastructure, with many other health benefits.

Sailing in Uncharted Waters: Carefully Navigating the Polio Endgame.

In a Perspective linked to the research article by Isobel Blake and colleagues, Elizabeth Miller and T. Jacob John discuss the path towards global polio eradication and the challenges, strategies, and necessary precautions around oral polio vaccine cessation.

Immunogenicity of a new routine vaccination schedule for global poliomyelitis prevention: an open-label, randomised controlled trial.

BACKGROUND: Polio eradication needs a new routine immunisation schedule--three or four doses of bivalent type 1 and type 3 oral poliovirus vaccine (bOPV) and one dose of inactivated poliovirus vaccine (IPV), but no immunogenicity data are available for this schedule. We aimed to assess immunogenicity of this vaccine schedule. METHODS: We did an open-label, randomised controlled trial in four centres in India. After informed consent was obtained from a parent or legally acceptable representative, healthy newborn babies were randomly allocated to one of five groups: trivalent OPV (tOPV); tOPV plus IPV; bOPV; bOPV plus IPV; or bOPV plus two doses of IPV (2IPV). The key eligibility criteria were: full-term birth (≥37 weeks of gestation); birthweight ≥2·5 kg; and Apgar score of 9 or more. OPV was administered at birth, 6 weeks, 10 weeks, and 14 weeks; IPV was administered intramuscularly at 14 weeks. The primary study objective was to investigate immunogenicity of the new vaccine schedule, assessed by seroconversion against poliovirus types 1, 2, and 3 between birth and 18 weeks in the per-protocol population (all participants with valid serology results on cord blood and at 18 weeks). Neutralisation assays tested cord blood and sera collected at 14 weeks, 18 weeks, 19 weeks, and 22 weeks by investigators masked to group allocation. This trial was registered with the India Clinical Trials Registry, number CTRI/2013/06/003722. FINDINGS: Of 900 newborn babies enrolled between June 13 and Aug 29, 2013, 782 (87%) completed the per-protocol requirements. Between birth and age 18 weeks, seroconversion against poliovirus type 1 in the tOPV group occurred in 162 of 163 (99·4%, 95% CI 96·6-100), in 150 (98·0%, 94·4-99·6) of 153 in the tOPV plus IPV group, in 153 (98·7%, 95·4-99·8) of 155 in the bOPV group, in 155 (99·4%, 96·5-100) of 156 in the bOPV plus IPV group, and in 154 (99·4%, 96·5-100) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 2 occurred in 157 (96·3%, 92·2-98·6) of 163 in the tOPV group, 153 (100%, 97·6-100·0) of 153 in the tOPV plus IPV group, 29 (18·7%, 12·9-25·7) of 155 in the bOPV group, 107 (68·6%, 60·7-75·8) of 156 in the bOPV plus IPV group, and in 121 (78·1%, 70·7-84·3) of 155 in the bOPV plus 2IPV group. Seroconversion against poliovirus type 3 was achieved in 147 (90·2%, 84·5-94·3) of 163 in the tOPV group, 152 (99·3%, 96·4-100) of 153 in the tOPV plus IPV group, 151 (97·4%, 93·5-99·3) of 155 in the bOPV group, 155 (99·4%, 96·5-100) of 156 in the bOPV plus IPV group, and 153 (98·7%, 95·4-99·8) of 155 in the bOPV plus 2IPV group. Superiority was achieved for vaccine regimens including IPV against poliovirus type 3 compared with those not including IPV (tOPV plus IPV vs tOPV alone, p=0·0008; and bOPV plus IPV vs bOPV alone, p=0·0153). 12 serious adverse events occurred (six in the tOPV group, one in the tOPV plus IPV group, three in the bOPV group, zero in the bOPV plus IPV group, and two in the bOPV plus 2IPV group), none of which was attributed to the trial intervention. INTERPRETATION: The new vaccination schedule improves immunogenicity against polioviruses, especially against poliovirus type 3. FUNDING: WHO, through a grant from Rotary International (grant number 59735).

Intestinal mucosal immunity is unimportant for polio eradication: the failure of oral polio vaccination.

AIMS: To explore if intestinal immunity induced by infection with live viruses in the oral poliovirus vaccine (OPV) is essential, necessary or even helpful in interrupting transmission of wild poliovirus (WPV) for global polio eradication. METHODS: We reviewed the biology of virus-host interactions in WPV infection and its alterations by OPV-induced immunity for direct evidence of the usefulness of intestinal immunity. We also explored indirect evidence by way of the effect of the inactivated poliovirus vaccine (IPV) on the biology and on transmission dynamics of WPV. RESULTS: Immunity, systemic and intestinal, induced by infection with WPV or vaccine viruses, does not prevent re-infection with WPV or vaccine viruses respectively, when exposed. Such re-infected hosts shed virus in the throat and in faeces and are sources of further transmission. Immunity protects against polio paralysis-hence reinfection always remain asymptommatic and silent. CONCLUSION: Vaccine virus-induced intestinal immunity is not necessary for polio eradication. The continued and intensive vaccination efforts using OPV under the assumption of its superiority over IPV have resulted in the well-known undesirable effects, namely vaccine associated paralytic polio and the emergence of de-attenuated circulating vaccine-derived polioviruses, in addition to the delay in completing global WPV eradication.

The Immunogenicity of Monovalent Oral Poliovirus Vaccine Type 1 (mOPV1) and Inactivated Poliovirus Vaccine (IPV) in the EPI Schedule of India.

BACKGROUND: In 2016, the Global Polio Eradication Initiative (GPEI) recommended the cessation of using type 2 oral poliovirus vaccine (OPV) and OPV, with countries having to switch from the trivalent to bivalent OPV (bOPV) with the addition of inactivated poliovirus vaccine (IPV) in their routine immunization schedule. The current GPEI strategy 2022-2026 includes a bOPV cessation plan and a switch to IPV alone or a combination of vaccine schedules in the future. The focus of our study was to evaluate the immunogenicity of monovalent OPV type 1 (mOPV1) with IPV and IPV-only schedules. METHODS: This was a three-arm, multi-center randomized-controlled trial conducted in 2016-2017 in India. Participants, at birth, were randomly assigned to the bOPV-IPV (Arm A) or mOPV1-IPV (Arm B) or IPV (Arm C) schedules. Serum specimens collected at birth and at 14, 18, and 22 weeks old were analyzed with a standard microneutralization assay for all the three poliovirus serotypes. RESULTS: The results of 598 participants were analyzed. The type 1 cumulative seroconversion rates four weeks after the completion of the schedule at 18 weeks were 99.5% (97.0-99.9), 100.0% (97.9-100.0), and 96.0% (92.0-98.1) in Arms A (4bOPV + IPV), B (4mOPV1 + IPV), and C (3IPV), respectively. Type 2 and type 3 seroconversions at 18 weeks were 80.0% (73.7-85.1), 76.9% (70.3-82.4); 93.2% (88.5-96.1), 100.0% (98.0-100.0); and 81.9% (75.6-86.8), 99.4% (96.9-99.9), respectively, in the three arms. CONCLUSIONS: This study shows the high efficacy of different polio vaccines for serotype 1 in all three schedules. The type 1 seroconversion rate of mOPV1 is non-inferior to bOPV. All the vaccines provide high type-specific immunogenicity. The program can adopt the use of different vaccines or schedules depending on the epidemiology from time to time.

Eradicating poliomyelitis: India's journey from hyperendemic to polio-free status.

India's success in eliminating wild polioviruses (WPVs) has been acclaimed globally. Since the last case on January 13, 2011 success has been sustained for two years. By early 2014 India could be certified free of WPV transmission, if no indigenous transmission occurs, the chances of which is considered zero. Until early 1990s India was hyperendemic for polio, with an average of 500 to 1000 children getting paralysed daily. In spite of introducing trivalent oral poliovirus vaccine (tOPV) in the Expanded Programme on Immunization (EPI) in 1979, the burden of polio did not fall below that of the pre-EPI era for a decade. One of the main reasons was the low vaccine efficacy (VE) of tOPV against WPV types 1 and 3. The VE of tOPV was highest for type 2 and WPV type 2 was eliminated in 1999 itself as the average per-capita vaccine coverage reached 6. The VE against types 1 and 3 was the lowest in Uttar Pradesh and Bihar, where the force of transmission of WPVs was maximum on account of the highest infant-population density. Transmission was finally interrupted with sustained and extraordinary efforts. During the years since 2004 annual pulse polio vaccination campaigns were conducted 10 times each year, virtually every child was tracked and vaccinated - including in all transit points and transport vehicles, monovalent OPV types 1 and 3 were licensed and applied in titrated campaigns according to WPV epidemiology and bivalent OPV (bOPV, with both types 1 and 3) was developed and judiciously deployed. Elimination of WPVs with OPV is only phase 1 of polio eradication. India is poised to progress to phase 2, with introduction of inactivated poliovirus vaccine (IPV), switch from tOPV to bOPV and final elimination of all vaccine-related and vaccine-derived polioviruses. True polio eradication demands zero incidence of poliovirus infection, wild and vaccine.

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.

Extensively drug-resistant tuberculosis in India: a review.

BACKGROUND & OBJECTIVES: Extensively drug resistant tuberculosis (XDR-TB) has become a new threat for the control of TB in many countries including India. Its prevalence is not known in India as there is no nation-wide surveillance. However, there have been some reports from various hospitals in the country. METHODS: We have reviewed the studies/information available in the public domain and found data from 10 tertiary care centres in 9 cities in India. RESULTS: A total of 598 isolates of XDR Mycobacterium tuberculosis have been reported in the studies included. However, the reliability of microbiological methods used in these studies was not checked and thus the XDR-TB data remained invalidated in reference laboratories. INTERPRETATION & CONCLUSIONS: Systematic surveillance and containment interventions are urgently needed.

Lessons from Vaccine-Related Poliovirus in Israel, UK and USA.

Genetic variants of vaccine poliovirus type 2, imported from an unknown source, were detected in waste waters in Jerusalem, London and New York in early 2022. Wild poliovirus type 2 was globally eradicated in 1999, but vaccine virus type 2 continued for 16 more years; routine use of the vaccine was discontinued in 2016 and reintroduced occasionally on purpose. As an unintended consequence, type 2 vaccine virus variants (circulating vaccine-derived polioviruses, cVDPVs) that mimic wild viruses' contagiousness and neurovirulence, have been emerging and spreading. To illustrate, in just the past four years (2018-2021), 2296 children developed cVDPV polio in 35 low-income countries. Many assume that virus transmission is via the faecal-oral route. Sustained virus transmission was documented in London and New York, in spite of high standards of sanitation and hygiene. Here, virus transmission cannot be attributed to faecal contamination of food or drinking water (for faecal-oral transmission). Hence, contagious transmission can only be explained by inhalation of droplets/aerosol containing virus shed in pharyngeal fluids (respiratory transmission), as was the classical teaching of polio epidemiology. If transmission efficiency of VDPV is via the respiratory route where hygiene is good, it stands to reason that it is the same case in countries with poor hygiene, since poor hygiene cannot be a barrier against respiratory transmission. By extrapolation, the extreme transmission efficiency of wild polioviruses must also have been due to their ability to exploit respiratory route transmission. These lessons have implications for global polio eradication. It was as a result of assuming faecal-oral transmission that eradication was attempted with live attenuated oral polio vaccine (OPV), ignoring its safety problems and very low efficacy in low-income countries. Inactivated poliovirus vaccine (IPV) is completely safe and highly efficacious in protecting children against polio, with just three routine doses. Protecting all children from polio must be the interim goal of eradication, until poliovirus circulation dies out under sustained immunisation pressure. OPV should be discontinued under cover of immunity induced by IPV to stop the emergence of new lineages of VDPVs, not only type 2, but also types 1 and 3, to expedite the completion of polio eradication.

Timely use of Covid-19 vaccines could have saved thousands of lives.

Earlier we, TJJ and DD, had written in IJME, that during the pandemic with high case-fatality in those above 65 and younger adults with chronic lung, heart or kidney diseases or diabetes, vaccination must be administered early as a life-saving procedure (1). It was pointed out that protection delayed may be protection denied to drive home the urgency of vaccination for saving lives. At that time, Phase III vaccine trials were in progress and we had adequate data on safety, but efficacy had yet to be measured. Good immunogenicity had already been documented in Phases I and II in which there were no signals of safety problems. Efficacy was "on promise" when we argued for early vaccination of those at risk of death.

The role of research in viral disease eradication and elimination programs: lessons for malaria eradication.

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases--smallpox, poliomyelitis, and measles--we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios.

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.

COVID-19 Eradication for Vaccine Equity in Low Income Countries.

The coronavirus disease 2019 (COVID-19) pandemic will transition into endemic phase with perpetual risk of severe disease and high mortality in vulnerable people - the elderly and those with co-morbidities, unless eradicated. Although several vaccines are already available to rich countries, low-income countries face gross vaccine inequity. We propose COVID-19 eradication to address both problems. An eradication program will ensure vaccine equity and international cooperation to establish public health surveillance and high quality laboratory diagnostic services in all countries. Eradication is biologically and technically feasible. We hope the World Health Organization will accept the proposition and design the necessary strategy without delay.