The bacterium Bordetella pertussis is the most common cause of pertussis or whooping cough and it spreads from an infected person’s cough or sneeze as airborne droplets.
Some (Australia, Canada, Ireland, Spain, UK, US), not all, countries that switched from whole cell (wP) to acellular (aP) pertussis vaccines saw in subsequent decades (),
- Protection that turned out to be both weaker and of shorter duration in adolescents.
- Resurgence of pertussis infections, even among those previously vaccinated, i.e., poor herd immunity.
Not only does aP appear to induce weak immunological memory against pertussis in these countries, it even appears to be counter-productive in some age groups. Italy, Japan and Sweden are reported exceptions to these trends ().
Why did some countries decide to switch from wP to aP in the first place?
In the US, that decision was not rooted in scientific rationale but was instead a knee-jerk reaction by vaccine manufacturers and government regulators to lawsuits in the 1980s.
Developed in the 1930s, wP is just killed Bordetella pertussis bacteria and it does give injection site reactions. This was enough for some US parents in the 1980s to blame it for encephalopathy-associated febrile seizures and intellectual disability in their children. The resulting lawsuits drove most US pertussis vaccine manufacturers out of the market and made it urgent for the US to find a ‘safer’ vaccine alternative.
Simply removing the Bordetella pertussis cell wall component, endotoxin, presumed responsible for the injection site reactions, presented itself as the easy solution, never mind that it wasn’t the source of the febrile seizures, whose cause(s) remained unidentified. The eventual approved product, aP, had some purified pertussis antigens but not the endotoxin.
Meantime, recent discoveries suggest switching from wP to aP was based on a fallacy since a causal link between wP and febrile seizures seems to have been misplaced.
An exhaustive retrospective 2010 analysis concluded that children who had developed such seizures coincident to wP instead had, de novo mutations in the sodium channel gene SCN1A ( ). This conclusion was strengthened by the observation that children who got wP before or after their first seizure had similar clinical outcome when consequences of pre-seizure wP should have been worse if it indeed played a role in the syndrome.
Confirmation bias may thus have played a role in implicating wP in these febrile seizures. After all, wP is still standard for large swaths of the world’s population such as India, which haven’t reported febrile seizures after children there get wP.
Nevertheless, naysayers would argue such retrospective studies include small numbers of patients, that they rely on previously recorded clinical data and thus may be subject to recall bias, and that they lack an unvaccinated control group.
Point is the horse is already out of the barn and these days, parents in countries such as the US are less likely or even unlikely to agree to switching back to wP even as data accumulates that it does indeed better protect against pertussis infection compared to aP.
Constituents of effective human anti-pertussis immunity are still unknown
Usually intended for use among the healthy population at large makes vaccines a much more expensive proposition compared to drugs and other medical interventions. Optimal scientific proof that a vaccine indeed prevents a given infection requires comparing infection rates for many years, maybe even lifetimes, in two groups, one that got the vaccine and the other that didn’t, an unimaginably expensive proposition that would make it impossible to get any vaccine approved.
Vaccinologists counter this gap by developing protection measurements assumed to be reliable surrogates.are immunological assays that hopefully measure the relevant anti-vaccine immune response(s).
Countries such as the US switching from wP to aP relied on such pertussis-related correlates of protection for their decision making. Specifically, they concluded that aP induced equivalent immunity compared to wP since both induced equivalent antibody titers against the pertussis antigens present in aP.
Contrary to anti-vaxxer conspiracy theories, vaccines are actually loss-leaders rather than moneymaking bonanzas for pharma companies. It isn’t by accident that at ~US $17 billion, vaccines represent barely 3% of US pharmaceutical sales ().
Problem is rodent animal models commonly used in pertussis are poorly predictive of human infection and immunity. Baboons may be a better model but using them is both prohibitively expensive and ethically problematic.
That perverse incentives fuel scientific research doesn’t help matters either, with knowledge about the mouse immune system leaps and bounds ahead of its human counterpart.
Thus, pertussis vaccinologists have been making decisions in the dark, not knowing exactly which human immune responses are relevant and/or critical for preventing infection nor knowing which pertussis antigens are necessary and sufficient to recapitulate effective immunity against the whole organism. Today decades later, such ignorance is proving costly since data shows that antibody titers against aP antigens, assumed to be a reliable correlate of protection, are unable to distinguish between effective (driven by wP) and ineffective (driven by aP) human anti-pertussis immune responses.
What then lies behind the push to vaccinate adults with aP to protect babies?
Maternal pertussis vaccination effectively protects against infant death from pertussis (, ), especially when it is given in the 2nd trimester ( ).
Since the US switch to aP largely occurred in the late 1990s and early 2000s, the idea is today’s mothers as well as older adults were more likely to have been primed (originally vaccinated) with wP, meaning they should have a more robust and effective pre-existing memory immune response to pertussis. Meantime, studies have shown that even a single aP boost can effectively reactivate memory immune responses initially induced by wP ().
This is the basis for the rationale that expectant mothers boosted with even a less than optimal aP may passively transfer sufficient levels of anti-pertussis antibodies to vulnerable infants to protect them from pertussis.
Problem is the window of opportunity for such an approach is fast closing as aP-primed girls grow up and become mothers. Given the poor ability of aP to prime strong and effective anti-pertussis immunity, it’s unclear whether an aP boost given during pregnancy to aP-primed mothers would work as well.
At their core, suspicions about vaccines represent a profound failure of communication and breakdown of trust between scientists and those who harbor such suspicions. Since vaccines affect pubic health, entire populations, not just those individuals, pay the price.
Perversely, science’s successes – not just vaccines but also hygiene and sanitation – set the stage for current doubts about vaccines among some individuals in affluent countries. After all, at least one or more generations of people in affluent countries such as the US have now grown up without facing the scourge of epidemics caused by pathogenic microbes. Such an embarrassment of riches can foster unreasonable expectations.
In the case of vaccines, that unreasonable expectation expresses itself as entitlement to paramount safety and zero risk, notwithstanding that being very far from complete, current knowledge of human biology could never hope to meet such a lofty expectation.
In response, vaccine makers and regulators alike feel pressured to make the more risk-averse and biologically impossible decision of prioritizing safety over immunogenicity when designing new vaccines, the decision to switch from wP to aP being a case in point. This ends up violating an essential biological principle since immunogenicity, the ability to drive strong and effective immune responses, requires ‘dirt’.
Needing to make up for this lack of natural ‘dirt’, scientists addto sub-unit vaccines comprised of pure antigens. However, how adjuvants work is still largely a black box which means outcomes remain unpredictable, especially at a population level. The wP to aP switch embodies these drawbacks.
For more details on the why and consequences of switching from wP to aP:
1. Gill, Christopher, Pejman Rohani, and Donald M. Thea. “The relationship between mucosal immunity, nasopharyngeal carriage, asymptomatic transmission and the resurgence of Bordetella pertussis.” F1000Research 6 (2017).
2. McIntosh, Anne M., et al. “Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study.” The Lancet Neurology 9.6 (2010): 592-598.
4. Amirthalingam, Gayatri, et al. “Effectiveness of maternal pertussis vaccination in England: an observational study.” The Lancet 384.9953 (2014): 1521-1528.
5. Dabrera, Gavin, et al. “A case-control study to estimate the effectiveness of maternal pertussis vaccination in protecting newborn infants in England and Wales, 2012–2013.” Clinical Infectious Diseases 60.3 (2014): 333-337.
6. Eberhardt, Christiane S., et al. “Maternal immunization earlier in pregnancy maximizes antibody transfer and expected infant seropositivity against pertussis.” Clinical Infectious Diseases 62.7 (2016): 829-836.
7. Huang, Li-Min, et al. “Immunogenicity and reactogenicity of a reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine in healthy Taiwanese children and adolescents.” Journal of Adolescent Health 37.6 (2005): 517-e1.