Polio eradication & regular childhood immunization

For decades there has existed tension between primary healthcare (PHC) and selective disease control (SDC) approaches for public health in low- and middle-income (LMI) countries [1,2]. The Expanded Program on Immunization (EPI) provided a model platform for combining the two for synergistic functional effectiveness. In fact, EPI grew out of smallpox eradication, which was both the success model of SDC and a telling testimony of the power of vaccines. When polio was identified and targeted for eradication, it was the first test of the new synergistic model of PHC plus SDC [3]. In theory, global polio eradication (GPE) was to be the crowning glory of EPI but, in practice, it was distanced from it as another SDC program. The tension had to be addressed and resolved but it was not. The world continues to pay the hefty price of that unwise choice.

The World Health Assembly, most WHO experts and the early leadership of GPE apparently failed to perceive this tension while designing the program. They took it rather as a mere choice between the two vaccines against polio, the injectable polio vaccine (IPV) and the oral polio vaccine (OPV), and the latter was chosen for exclusive use in all LMI countries practicing EPI [4]. High-income countries using OPV achieved polio elimination in two stages: first interrupting wild poliovirus (WPV) transmission using OPV through regular vaccination programs, and later eliminating vaccine virus infection using IPV [5,6]. We will refer to them as stage W and V, respectively [7,8]. High-income Northern European countries achieved both stages simultaneously using IPV exclusively in their regular vaccination program [9,10].

Had IPV been adopted in GPE in LMI countries too, the design would have depended on, thus ensuring, the functional efficiency of the EPI. This would have resulted in a high level of control of WPV transmission, if not interruption. If needed, OPV in pulse campaigns could have been used for completing interruption of WPV transmission and then withdrawn. In this scenario, the program could have achieved both stages of GPE either together or sequentially. The SDC approach ignoring EPI may have seemed expedient at first, but its repercussions are difficult to overcome. A functionally efficient EPI using IPV appears to be essential both for achieving stage V eradication and for sustaining GPE; so the original tension has not disappeared. The need for re-invigoration of EPI was merely postponed. Delayed completion of any project escalates cost – GPE included.

Merits & defects of OPV

The OPV is one of the cheapest vaccines and is easiest to inoculate as oral drops. Under refrigeration, it has a long shelf life. No age restriction need be observed in childhood vaccination – from birth to any need-based upper age. It causes no pain, fever, discomfort or diarrhea. Apparently, it looked like an ideal vaccine to the untrained eyes.

Interestingly, OPV exhibits wide variations in vaccine efficacy (VE), with striking geographic distribution [11,12]. Where the force of transmission (FoT) of WPV was low, the VE of OPV was high and its use in regular childhood vaccination was sufficient to interrupt WPV transmission. Unfortunately, where the FoT of WPV is high, the VE of OPV is low, as in many LMI countries concentrated in the tropical and subtropical belt [11,12]. Thus, it is not surprising that all currently WPV-endemic countries (India, Pakistan, Afghanistan and Nigeria) and others that had failed to eliminate WPV transmission by 2000 (Egypt, Niger and Somalia) belong to this category.

The aformentioned countries that continue to have WPV circulation have two major problems, namely low OPV efficacy and low coverage of OPV by schedule under EPI; the comparative importance of the two varies in each locale [13]. To improve VE, several repeated doses of OPV, trivalent and/or monovalent, are given; the improvement of VE is proportional to the number of doses of OPV, which in turn is a function of age [12,14]. The number of doses and VE improve as age increases. The most critical age ‘substrate’ for WPV infection, amplification and transmission (thus circulation) in India and Pakistan is infants under 6 months, which is the prime target age for EPI schedule doses [12,15]. Where EPI is weak and VE is low, the synergy between the two adverse forces is formidable in this age cohort, compounded by high birth rates feeding more substrate fast into the mix; as in the fertile river valley regions of UP-Bihar of India and Punjab-Sind of Pakistan [13]. Even if 100% of older children are immune, these infants can maintain WPV circulation provided population density and birth rate are high.

Another inherent property of OPV is the propensity to de-attenuation – manifested by the rare (vaccinated) child with vaccine-virus polio and by other children (or adults) with sporadic polio caused by community-acquired vaccine virus infection, proving secondary transmission from the vaccinated children [16]. If transmission continues by chance in further generations, such a virus may gain the ability for efficient circulation, mimicking WPV [17]. In parallel, neurovirulence is retrieved through genetic mutations during repeated cycles of virus multiplication [17]. The resultant circulating vaccine-derived polioviruses (cVDPV) can cause polio outbreaks, rather like WPV. These properties call for discontinuation of OPV in order to achieve the (second) stage V of polio eradication, as well as (as far as our knowledge and experience go) the widespread use of IPV [7]. In the last two decades, over 35 countries (with relatively high income) have switched from OPV to IPV in their national childhood vaccination programs and they were able to achieve stage V without cVDPV, thus providing the only model of safe transition for other countries [5,6,18].

Merits & defects of IPV

The VE of IPV is high everywhere, with little geographic variation. It is completely safe. Where VE of OPV is problematic, IPV provides predictably high VE [19–21]. Since it can be presented in combination with the diphtheria–tetanus–pertussis (DTP) vaccine, it is EPI-friendly [19–21]. However, the present EPI schedule of 6–10–14 weeks is not the best for IPV response for two reasons: at 6 weeks there would be sufficient maternal antibody in a proportion of infants that inhibits sensitization with the first dose; and a 4-week interval is not optimum for the prime–boost response of any vaccine [22]. If given at or after 8 weeks of age and if the interval is increased to 8 or more weeks, even two doses would elicit near-100% seroconversion [23]. Given even at 6–10–14 weeks, the three-dose schedule offers satisfactory seroconversion frequency (which is far superior to that of three doses of OPV) in LMI countries [12,22]. In reality, many infants start EPI vaccinations after some delay; thus, DTP–IPV combination is suitable for EPI and campaigns are not needed.

Two disadvantages have been described. One, the production cost of IPV is more than that of OPV and, therefore, the price is also higher. The selling price is not the same as production cost but, even under the best of circumstances (competition among manufacturers and high-volume production, among others), the per-dose price of IPV will remain greater than that of OPV. On the other hand, the reduced number of doses and the combined formulation that avoids additional storage space and injections reduce the overall cost of polio vaccination.

The second frequently quoted disadvantage is that IPV induces inferior intestinal mucosal (IgA-mediated) immunity compared with OPV. This is to be expected as the local IgA response is stimulated by local infection. Therefore, some experts suspect that IPV may not offer the herd effect – retardation of WPV circulation speedier than that of vaccine coverage. This is false logic for several reasons. An excellent herd effect had been recorded wherever IPV was used on a large scale [12,19–21]. High VE, a prerequisite for the herd effect, is shown only by IPV but not OPV in tropical developing countries. The herd effect of OPV is expressed only where its VE is high and the FoT of WPV transmission is low, in temperate-zone high-income countries. Where most needed, OPV exhibits no herd effect and virtually every child has to be repeatedly inoculated to retard WPV circulation [24]. Furthermore, WPV circulation does not appear to be predominantly fecal–oral, as widely taught, but contagious (person to person). The facts that childhood populations are saturated with WPV infection by the age of 5 years universally in all developing countries, the very high infection frequency in infancy with median age of 12–18 months, the lack of polio control with improved sanitation in rich countries and the paucity of water-borne or food-borne outbreaks clearly point to contagious transmission and not fecal–oral circulation. Therefore, intestinal mucosal immunity is not important for herd effect. The nasopharyngeal mucosal immunity, necessary for reducing contagious transmission, hence herd effect, is more prominent after IPV than OPV [9,10,25].

The fact that IPV is injected and not campaign friendly is no disadvantage, as it needs fewer doses than OPV for immune protection and neither campaigns nor repetitive doses are necessary.

Dilemmas of the present & future

We cannot retread the past but can redesign the future. We are approaching the close of the first decade of the 21st Century but GPE has not yet succeeded, despite the time target being the end of the last century. We can proceed only from where we are now – no amount of regret or recrimination will help reconstruction. There are no simple solutions to complex problems.

The four countries, India, Pakistan, Afghanistan and Nigeria, present formidable obstructions to achieving stage W of eradication. This is one problem to overcome. A second problem is to safely withdraw all OPV once the former is achieved. The risk of cVDPV emerging after discontinuing OPV has to be pre-empted as best as possible. The scientific assessment of the potential contribution by introducing IPV, the program redesign for feasibility and costing, budget and fund raising all need to be considered by the GPE leadership to address both problems.

In this issue of Expert Review of Vaccines[26], Paul writes about the delay in interrupting WPV in India and enumerates a number of possible reasons why OPV has not performed effectively in the UP-Bihar belt. The paper is a signal that many pediatricians have lost faith in OPV and want to introduce IPV as soon as possible. This brings to focus the tension described earlier: should the reforms of EPI wait until after polio is eradicated or should it be instituted in parallel track with polio eradication? Weak EPI is an impediment for the introduction of IPV in the problem states (and countries). Although IPV could be used in campaign mode to achieve rapid interruption of WPV, de-linked from EPI, how do we sustain it without a well-performing EPI?

A decision regarding the future need and use of IPV is extremely urgent [8,15]. If deemed necessary, then it can be introduced early not only to achieve stage V but also to help expedite stage W. If, on the other hand, IPV is deemed unnecessary in the future in LMI countries, then the leadership has to choose between achieving stage W by the exclusive use of OPV – trivalent, bivalent and monovalent [14] – and limited additional use of IPV, if found necessary. My personal opinion is that the huge investment in GPE must be protected with the universal (or at least very wide) use of IPV [7,8,19–21]. This is the only model we have for safe transition to stage V eradication and to minimize, if not abrogate, future risk of the development, evolution and spread of cVDPV [5,6,18]. Practicality dictates that it be best established using combination DTP–IPV before OPV is finally withdrawn. Therefore, now is the time to re-engineer EPI to accommodate IPV and achieve high coverage – this should go hand in hand with the pursuit of polio eradication. It will be essential to achieve high enough coverage (∼85–90%) according to schedule (<6 months of age), in order to apply the excellent VE of IPV and its consequent herd effect to control through to interruption of transmission of polioviruses, wild and vaccine. The current weaknesses of EPI must be investigated, enumerated and fixed in order to accommodate IPV and achieve high coverage. This will add value to GPE, which by itself should be, and be seen to be, the crowning glory of EPI – in its 21st Century avatar.

If universal IPV is not feasible, as many countries as possible should be encouraged to introduce it. The greater the total population under IPV cover, the less the probability of cVDPV emergence. Most WHO European Region countries and a few countries in the Americas and Western Pacific Regions are currently using only IPV; hence, all of Europe, the Americas and Western Pacific Regions are ripe for the transition. The next region that could adopt this step is Eastern Mediterranean and later South East Asian. Finally, it will be the turn of the African Region. Most, if not many, of the countries in the first five regions are economically sufficiently well-off to budget the transition – international funding will be necessary for some countries, but not all.

Every solution brings new problems. Currently, IPV is made from fully virulent laboratory-stocked WPV and in a poliovirus-free world that poses some risk of ‘escape’. However, ensuring bio-containment at manufacturing sites is eminently possible. Making IPV with OPV viruses is another approach that is currently progressing as research. Presently, the price of IPV is exorbitant, but there are ways of reducing it to meet the world needs. Currently, the popular version of DTP–IPV is with the acellular pertussis (aP) vaccine, which is much costlier than the whole-cell pertussis (wP) vaccine. Reducing the cost of aP or making combination with wP is not an insoluble problem.

Immediate next step

The immediate call is for a retreat of GPE and WHO leadership, along with the partners, namely the UNICEF, Rotary International and the US CDC, all major donors, representatives from key LMI countries and experts in epidemiology and management to discuss thoroughly all the above issues (and others I have not covered) and answer the questions. Such a retreat was not attempted initially – due perhaps to the overconfidence of the partners and their misplaced faith in one vaccine to the exclusion of the second. When two excellent tools of intervention were available, the issue was not one of competition but complementary application.

The sooner the world completes and concludes GPE, the sooner we can shift gears to eradicate measles and effectively control (and prove by routine surveillance the control of) all other vaccine-targeted infectious diseases. The inclusion of newer vaccines in EPI in LMI countries requires a robust EPI, which, at least in part, depends on successful polio eradication.