Vaccines from the Spanish Influenza as a firm foundation for new developments.

In 1914, the concept of a prophylactic vaccine, administered to a person before the disease had been contracted, was still controversial. Nevertheless, Almroth Wright tested new pneumococcus vaccines in South Africa, where the incidence of bacterial pneumonia was high amongst workers in the gold mines. He established the use of clinical trials, using around ten thousand workers, both in vaccinated and unvaccinated groups. The two groups were not matched to modern standards. Also, of course, those workers in the control unvaccinated group could not be protected: but some considered a prophylactic vaccine would exacerbate the disease. The vaccines were manufactured to contain a range of pneumococci from different clinical samples, in a serious attempt to match the microbes in the vaccine to the field bacteria. Deaths were averted by the vaccine; and side effects were noted to be minimal. Reexamination of pathology samples from the Spanish Influenza Pandemic showed quite clearly the contribution of pneumococci and streptococci to the mortality of over fifty million people in 1918-1919. The microbe causing this Pandemic was isolated in 1933, and was shown to be a true virus; this finding initiated a huge expanse and interest in influenza virus vaccines, both killed and live. A chance discovery allowed the purification of Influenza M and NP proteins then permitted the production of experimental vaccines. These vaccines were formulated to induce and B and/or T cell responses to the internal proteins. Several of these Universal Influenza Vaccines have been tested in quarantine, and have now reached Phase III trials in the community.

A possible European origin of the Spanish influenza and the first attempts to reduce mortality to combat superinfecting bacteria: an opinion from a virologist and a military historian.

When we reconsider the virology and history of the Spanish Influenza Pandemic, the science of 2018 provides us with tools which did not exist at the time. Two such tools come to mind. The first lies in the field of 'gain of function' experiments. A potential pandemic virus, such as influenza A (H5N1), can be deliberately mutated in the laboratory in order to change its virulence and spreadability. Key mutations can then be identified. A second tool lies in phylogenetics, combined with molecular clock analysis. It shows that the 1918 pandemic virus first emerged in the years 1915-1916. We have revisited the literature published in Europe and the United States, and the notes left by physicians who lived at the time. In this, we have followed the words of the late Alfred Crosby: who wrote that "contemporary documentary evidence from qualified physicians" is the key to understanding where and how the first outbreaks occurred. In our view, the scientists working in Europe fulfill Crosby's requirement for contemporary evidence of origin. Elsewhere, Crosby also suggested that "the physicians of 1918 were participants in the greatest failure of medical science in the twentieth century". Ours is a different approach. We point to individual pathologists in the United States and in France, who strove to construct the first universal vaccines against influenza. Their efforts were not misdirected, because the ultimate cause of death in nearly all cases flowed from superinfections with respiratory bacteria.

The origins of the great pandemic.

The timing and location of the first cases of the 1918 influenza pandemic are still controversial, a century after the pandemic became widely recognized. Here, we critically review competing hypotheses on the timing and geographical origin of this important outbreak and provide new historical insights into debates within military circles as to the nature of putative pre-1918 influenza activity. We also synthesize current knowledge about why the 1918 pandemic was so intense in young adults. Although it is still not clear precisely when and where the outbreak began and symptom-based reports are unlikely to reveal the answer, indirect methods including phylogenetics provide important clues, and we consider whether intense influenza activity as far back as 1915 in the USA may have been caused by viral strains closely related to the 1918 one.

Unanswered questions about the 1918 influenza pandemic: origin, pathology, and the virus itself.

The influenza epidemic of 1918 represented the greatest failure of medical science in the 20th century. Fortunately, research throughout subsequent years has been making amends. Some studies have applied RT-PCR to the tissue samples from that time, whereas others have reconstructed the pathogen in its virulent state. But the resurrection of the 1918 influenza virus leaves questions unanswered: although more virulent than contemporary H1N1 epidemic viruses in animal models, this increased virulence of the 1918 influenza virus is not sufficient to have been the sole cause of the high mortality rates recorded in humans during the epidemic. Thus, other hypotheses have been investigated. The immune history of the different age groups exposed at the time to the pandemic virus could be a factor, and the notion of original antigenic sin provides an explanation for the unusual pattern of deaths. The presence, or absence, of a cytokine storm in the lungs of young adults might also be involved. The time and location that the 1918 influenza pandemic first emerged from its avian reservoir is contentious, with arguments for China, Europe, and the USA, at various dates. Novel vaccines were tested during 1918, which are the precursors of the universal influenza vaccines that might offer protection in a future pandemic.

Ultralow crosstalk nanosecond-scale nested 2 × 2 Mach-Zehnder silicon photonic switch.

We present the design and characterization of a novel electro-optic silicon photonic 2×2 nested Mach-Zehnder switch monolithically integrated with a CMOS driver and interface logic. The photonic device uses a variable optical attenuator in order to balance the power inside the Mach-Zehnder interferometer leading to ultralow crosstalk performance. We measured a crosstalk as low as -34.5 dB, while achieving ∼2 dB insertion loss and 4 ns transient response.

Binary phase-shift keying by coupling modulation of microrings.

We propose a coupling-modulated microring in an add-drop configuration for binary phase-shift keying (BPSK), where data is encoded as 0 and π radian phase-shifts on the optical carrier. The device uses the π radian phase-flip across the zero coupling point in a 2 × 2 Mach-Zehnder interferometer coupler to produce the modulation. The coupling-modulated microring combines the drive power reduction of resonant modulators with the digital phase response of Mach-Zehnder BPSK modulators. A proof-of-concept device was demonstrated in silicon-on-insulator, showing differential binary phase-shift keying operation at 5 and 10 Gb/s.

Demonstration of electrooptic modulation at 2165nm using a silicon Mach-Zehnder interferometer.

We demonstrate electrooptic modulation at a wavelength of 2165nm, using a free-carrier injection-based silicon Mach-Zehnder modulator. The modulator has a V(π)∙L figure of merit of 0.12V∙mm, and an extinction ratio of -23dB. Optical modulation experiments are performed at bitrates up to 3Gbps. Our results illustrate that optical modulator design methodologies previously developed for telecom-band devices can be successfully applied to produce high-performance devices for a silicon nanophotonic mid-infrared integrated circuit platform.

Parallel-coupled dual racetrack silicon micro-resonators for quadrature amplitude modulation.

A parallel-coupled dual racetrack silicon micro-resonator structure is proposed and analyzed for M-ary quadrature amplitude modulation. The over-coupled, critically coupled, and under-coupled scenarios are systematically studied. Simulations indicate that only the over-coupled structures can generate arbitrary M-ary quadrature signals. Analytic study shows that the large dynamic range of amplitude and phase of a modulated over-coupled structure stems from the strong cross-coupling between two resonators, which can be understood through a delicate balance between the direct sum and the "interaction" terms. Potential asymmetries in the coupling constants and quality factors of the resonators are systematically studied. Compensations for these asymmetries by phase adjustment are shown feasible.

Generation and detection of 80-Gbit/s return-to-zero differential phase-shift keying signals.

Nonlinear polarization rotation between a pump and a probe signal in a highly nonlinear fiber is used as a modulation process to generate 80-Gbit/s return-to-zero differential phase-shift keying signals. Its performance is analyzed and compared with a conventional on-off keying modulated signal.

Broadband modulation of light by using an electro-optic polymer.

A major challenge to increasing bandwidth in optical telecommunications is to encode electronic signals onto a lightwave carrier by modulating the light up to very fast rates. Polymer electro-optic materials have the necessary properties to function in photonic devices beyond the 40-GHz bandwidth currently available. An appropriate choice of polymers is shown to effectively eliminate the factors contributing to an optical modulator's decay in the high-frequency response. The resulting device modulates light with a bandwidth of 150 to 200 GHz and produces detectable modulation signal at 1.6 THz. These rates are faster than anticipated bandwidth requirements for the foreseeable future.