After a 20 year search for parsimony, Hope-Simpson hypothesized that influenza is mainly transmitted by a limited number of highly infectious latent carriers – carriers infected the prior season – who are called into infectivity by a "seasonal stimulus" inextricably bound to sunlight and who remain highly infective for brief periods, thus explaining the waves of influenza that abruptly end despite a wealth of non-immune potential victims [2
]. Nevertheless, to our knowledge, researchers have never demonstrated latency for influenza, as expected with a constantly replicating RNA virus.
However, significant seasonal and population variations in innate immunity make it unnecessary to postulate latency to explain the bizarre epidemiology of influenza. While any theory of influenza must take into account four factors: transmissibility, virulence, adaptive immunity, and innate immunity, it has been easy to ignore innate immunity as it lacked demonstrable seasonal variations, population variations, and a mechanism of action.
To make sense of influenza's epidemiology, we revise Hope-Simpson theory, hypothesizing marked variation in the infectivity of the infected (the good infectors demonstrated in rats by Schulman and Kilbourne in 1963) and that vitamin D deficiency is Hope-Simpson's seasonal stimulus. Adding these two factors to transmissibility, virulence, and adaptive immunity, solves a number of influenza's mysteries.
1. Why is influenza both seasonal and ubiquitous and where is the virus between epidemics?
If influenza were surviving in an endless chain of transmissions from good transmitters to the well – the good transmitters being generally asymptomatic during times of enhanced innate immunity – the disease would be widely seeded in the population, explaining its ubiquity. Seasonal impairments in innate immunity would allow seasonal epidemics in temperate latitudes and less predictable epidemics in tropical zones, depending on viral novelty, transmissibility, virulence, and the innate immunity of the population. Non-seasonal isolated outbreaks would usually only appear in nursing homes [85
] or prisons [86
] where lack of sunlight impaired innate immunity; such isolated outbreaks would seldom lead to community outbreaks. More extensive out-of-season outbreaks, as occurred in 1918, would arise when novel antigenic viruses with significantly greater infectivity and virulence overwhelm innate immunity.
2. Why are influenza epidemics so explosive?
Predictable fall and winter impairments in innate immunity in temperate latitudes – and less predictable recurrent impairments in subequatorial and equatorial latitudes – would cause a percentage of the non-immune population to become suddenly susceptible to background influenza virus. The size of that susceptible subpopulation would vary, not only by the size of their impairments in innate immunity, but with the transmissibility and virulence of the virus, and the percentage of the population with competent adaptive immunity. Abrupt deficiencies in innate immunity, especially when large segments of the population also have inadequate adaptive immunity, would allow quiescent influenza to erupt.
3. Why do epidemics end so abruptly?
The rapid depletion of the population with both impaired innate and inadequate adaptive immunity may explain the abrupt disappearance of influenza. Impairments in innate immunity may also increase transmission, in effect, turning more infectors, symptomatic or not, into good transmitters. Furthermore, if only a small population of good transmitters – and not all the sick – usually spread the virus, and their transmission period is limited, the epidemic would end shortly after the good transmitters lose their infectivity.
4. What explains the frequent coincidental timing of epidemics in countries of similar latitudes?
Simultaneous impairments of innate immunity at similar latitudes – due to seasonal sunlight deprivation – explain the almost simultaneous eruption of influenza at sites of different longitude but similar latitude. If the virus had already imbedded itself in a population and a subgroup of the infected became good transmitters when their innate immunity declines to a critical threshold, such transmitters would coincidentally infect populations at similar latitudes made susceptible by those same impairments in innate immunity.
5. Why is the serial interval obscure?
Good transmitters explain the difficulty identifying influenza's serial interval especially since influenza's incubation period is well known. If only subpopulations of infected persons are good transmitters, and if their infectious period is limited, then the serial interval would remain obscure until we identified the good transmitters. Vitamin D induced variations in natural immunity may also affect influenza's incubation period, further obfuscating the serial interval.
6. Why is the secondary attack rate so low?
The studies we identified found a secondary attack rate of around 20%, impossibly low for a highly infectious virus spread from the sick to the well. If only a subpopulation of the infected, the good transmitters, are infective, this would explain the surprisingly low secondary attack rates. Current estimates of secondary attack rates assume the first case in the family is the index case and is spreading the disease. However, if only a subpopulation of infected persons transmit the disease, the true secondary attack rate could not be accurately determined until we identify the good infectors.
7. Why did epidemics in previous ages spread so rapidly, despite the lack of modern transport?
If influenza were embedded in the population, only to erupt when impairments in innate immunity create a susceptible subpopulation, the disease would only give the appearance of spreading. Instead, it would appear in large segments of the population seasonally, and almost simultaneously, as long as good transmitters were available. Furthermore, as good transmitters traveled, populations with neither adequate innate immunity nor competent adaptive immunity may succumb. That is, the disease would actually spread, as good transmitters traveled and subsequently infected well subpopulations with impaired immunity.
8. Why does experimental inoculation of seronegative humans fail to cause consistent illness?
If influenza is highly infectious, one would expect most, if not all, human volunteers iatrogenically inoculated with a novel virus to fall ill. Although the rate of illness depends on the virus used and the dose of the inoculum, variations in the innate immunity of the volunteers also explain such variable illness response. We propose individual variations in 25(OH)D levels explain some degree of the variations in illness response.
9. Over the last 20 years, why has influenza mortality in the aged not declined with increasing vaccination rates?
Given that influenza vaccines effectively improve adaptive immunity, the most likely explanation is that the innate immunity of the aged declined over the last 20 years due to medical and governmental warnings to avoid the sun. While the young usually ignore such advice, the elderly often follow it [87
]. We suggest that improvements in adaptive immunity from increased vaccination of the aged are inadequate to compensate for declines in innate immunity the aged suffered over that same time.