Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.

The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number of sublineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sublineages, BA.4 and BA.5, which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences, and although closely related to BA.2, they contain further mutations in the receptor-binding domain of their spikes. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by the serum from individuals vaccinated with triple doses of AstraZeneca or Pfizer vaccine compared with BA.1 and BA.2. Furthermore, using the serum from BA.1 vaccine breakthrough infections, there are, likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.

Specific CD4+ T cell phenotypes associate with bacterial control in people who 'resist' infection with Mycobacterium tuberculosis.

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ- T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4+ T cells showed enrichment of TH17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these TH17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype.

Onset of coupled atmosphere-ocean oxygenation 2.3 billion years ago.

The initial rise of molecular oxygen (O2) shortly after the Archaean-Proterozoic transition 2.5 billion years ago was more complex than the single step-change once envisioned. Sulfur mass-independent fractionation records suggest that the rise of atmospheric O2 was oscillatory, with multiple returns to an anoxic state until perhaps 2.2 billion years ago1-3. Yet few constraints exist for contemporaneous marine oxygenation dynamics, precluding a holistic understanding of planetary oxygenation. Here we report thallium (Tl) isotope ratio and redox-sensitive element data for marine shales from the Transvaal Supergroup, South Africa. Synchronous with sulfur isotope evidence of atmospheric oxygenation in the same shales3, we found lower authigenic 205Tl/203Tl ratios indicative of widespread manganese oxide burial on an oxygenated seafloor and higher redox-sensitive element abundances consistent with expanded oxygenated waters. Both signatures disappear when the sulfur isotope data indicate a brief return to an anoxic atmospheric state. Our data connect recently identified atmospheric O2 dynamics on early Earth with the marine realm, marking an important turning point in Earth's redox history away from heterogeneous and highly localized 'oasis'-style oxygenation.

Geographical migration and fitness dynamics of Streptococcus pneumoniae.

Streptococcus pneumoniae is a leading cause of pneumonia and meningitis worldwide. Many different serotypes co-circulate endemically in any one location1,2. The extent and mechanisms of spread and vaccine-driven changes in fitness and antimicrobial resistance remain largely unquantified. Here using geolocated genome sequences from South Africa (n = 6,910, collected from 2000 to 2014), we developed models to reconstruct spread, pairing detailed human mobility data and genomic data. Separately, we estimated the population-level changes in fitness of strains that are included (vaccine type (VT)) and not included (non-vaccine type (NVT)) in pneumococcal conjugate vaccines, first implemented in South Africa in 2009. Differences in strain fitness between those that are and are not resistant to penicillin were also evaluated. We found that pneumococci only become homogenously mixed across South Africa after 50 years of transmission, with the slow spread driven by the focal nature of human mobility. Furthermore, in the years following vaccine implementation, the relative fitness of NVT compared with VT strains increased (relative risk of 1.68; 95% confidence interval of 1.59-1.77), with an increasing proportion of these NVT strains becoming resistant to penicillin. Our findings point to highly entrenched, slow transmission and indicate that initial vaccine-linked decreases in antimicrobial resistance may be transient.

Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa.

The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively1-3. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function4. Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.

Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.

The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern1. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell-cell fusion2,3, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.

A 200-million-year delay in permanent atmospheric oxygenation.

The rise of atmospheric oxygen fundamentally changed the chemistry of surficial environments and the nature of Earth's habitability1. Early atmospheric oxygenation occurred over a protracted period of extreme climatic instability marked by multiple global glaciations2,3, with the initial rise of oxygen concentration to above 10-5 of the present atmospheric level constrained to about 2.43 billion years ago4,5. Subsequent fluctuations in atmospheric oxygen levels have, however, been reported to have occurred until about 2.32 billion years ago4, which represents the estimated timing of irreversible oxygenation of the atmosphere6,7. Here we report a high-resolution reconstruction of atmospheric and local oceanic redox conditions across the final two glaciations of the early Palaeoproterozoic era, as documented by marine sediments from the Transvaal Supergroup, South Africa. Using multiple sulfur isotope and iron-sulfur-carbon systematics, we demonstrate continued oscillations in atmospheric oxygen levels after about 2.32 billion years ago that are linked to major perturbations in ocean redox chemistry and climate. Oxygen levels thus fluctuated across the threshold of 10-5 of the present atmospheric level for about 200 million years, with permanent atmospheric oxygenation finally arriving with the Lomagundi carbon isotope excursion at about 2.22 billion years ago, some 100 million years later than currently estimated.

Detection of a SARS-CoV-2 variant of concern in South Africa.

Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.

Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma.

SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations1,2 and may reduce the efficacy of current vaccines that target the spike glycoprotein of SARS-CoV-23. Here, using a live-virus neutralization assay, we compared the neutralization of a non-VOC variant with the 501Y.V2 VOC (also known as B.1.351) using plasma collected from adults who were hospitalized with COVID-19 during the two waves of infection in South Africa, the second wave of which was dominated by infections with the 501Y.V2 variant. Sequencing demonstrated that infections of plasma donors from the first wave were with viruses that did not contain the mutations associated with 501Y.V2, except for one infection that contained the E484K substitution in the receptor-binding domain. The 501Y.V2 virus variant was effectively neutralized by plasma from individuals who were infected during the second wave. The first-wave virus variant was effectively neutralized by plasma from first-wave infections. However, the 501Y.V2 variant was poorly cross-neutralized by plasma from individuals with first-wave infections; the efficacy was reduced by 15.1-fold relative to neutralization of 501Y.V2 by plasma from individuals infected in the second wave. By contrast, cross-neutralization of first-wave virus variants using plasma from individuals with second-wave infections was more effective, showing only a 2.3-fold decrease relative to neutralization of first-wave virus variants by plasma from individuals infected in the first wave. Although we tested only one plasma sample from an individual infected with a SARS-CoV-2 variant with only the E484K substitution, this plasma sample potently neutralized both variants. The observed effective neutralization of first-wave virus by plasma from individuals infected with 501Y.V2 provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.

Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women.

Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.

Local exposure to inequality raises support of people of low wealth for taxing the wealthy.

Psychological research shows that social comparison of individuals with peers or others shapes attitude formation1,2. Opportunities for such comparisons have increased with global inequality3,4; everyday experiences can make economic disparities more salient through signals of social class5,6. Here we show that, among individuals with a lower socioeconomic status, such local exposure to inequality drives support for the redistribution of wealth. We designed a placebo-controlled field experiment conducted in South African neighbourhoods in which individuals with a low socioeconomic status encountered real-world reminders of inequality through the randomized presence of a high-status car. Pedestrians were asked to sign a petition to increase taxes on wealthy individuals to help with the redistribution of wealth. We found an increase of eleven percentage points in the probability of signing the petition in the presence of inequality, when taking into account the experimental placebo effect. The placebo effect suppresses the probability that an individual signs the petition in general, which is consistent with evidence that upward social comparison reduces political efficacy4. Measures of economic inequality were constructed at the neighbourhood level and connected to a survey of individuals with a low socioeconomic status. We found that local exposure to inequality was positively associated with support for a tax on wealthy individuals to address economic disparities. Inequality seems to affect preferences for the redistribution of wealth through local exposure. However, our results indicate that inequality may also suppress participation; the political implications of our findings at regional or country-wide scales therefore remain uncertain.

Paleolakes and socioecological implications of last glacial "greening" of the South African interior.

Determining the timing and drivers of Pleistocene hydrological change in the interior of South Africa is critical for testing hypotheses regarding the presence, dynamics, and resilience of human populations. Combining geological data and physically based distributed hydrological modeling, we demonstrate the presence of large paleolakes in South Africa's central interior during the last glacial period, and infer a regional-scale invigoration of hydrological networks, particularly during marine isotope stages 3 and 2, most notably 55 to 39 ka and 34 to 31 ka. The resulting hydrological reconstructions further permit investigation of regional floral and fauna responses using a modern analog approach. These suggest that the climate change required to sustain these water bodies would have replaced xeric shrubland with more productive, eutrophic grassland or higher grass-cover vegetation, capable of supporting a substantial increase in ungulate diversity and biomass. The existence of such resource-rich landscapes for protracted phases within the last glacial period likely exerted a recurrent draw on human societies, evidenced by extensive pan-side artifact assemblages. Thus, rather than representing a perennially uninhabited hinterland, the central interior's underrepresentation in late Pleistocene archeological narratives likely reflects taphonomic biases stemming from a dearth of rockshelters and regional geomorphic controls. These findings suggest that South Africa's central interior experienced greater climatic, ecological, and cultural dynamism than previously appreciated and potential to host human populations whose archaeological signatures deserve systematic investigation.

From virus structure to chromatin: X-ray diffraction to three-dimensional electron microscopy.

Early influences led me first to medical school with a view to microbiology, but I felt the lack of a deeper foundation and changed to chemistry, which in turn led me to physics and mathematics. I moved to the University of Cape Town to work on the X-ray crystallography of some small organic compounds. I developed a new method of using molecular structure factors to solve the crystal structure, which won me a research studentship to Trinity College Cambridge and the Cavendish Laboratory. There I worked on the austenite-pearlite transition in steel. This is governed by the dissipation of latent heat, and I ended up numerically solving partial differential equations. I used the idea of nucleation and growth during the phase change, which had its echo when I later tackled the assembly of Tobacco mosaic virus (TMV) from its constituent RNA and protein subunits. I wanted to move on to X-ray structure analysis of large biological molecules and obtained a Nuffield Fellowship to work in J.D. Bernal's department at Birkbeck College, London. There, I met Rosalind Franklin, who had taken up the study of TMV. I was able to interpret some of Franklin's beautiful X-ray diffraction patterns of the virus particle. From then on, my fate was sealed. After Franklin's untimely death in 1958, I moved in 1962 to the newly built MRC Laboratory of Molecular Biology in Cambridge, which, under Max Perutz, housed the original MRC unit from the Cavendish Laboratory. I was thus privileged to join the Laboratory at an early stage in its expansion and consequently able to take advantage of, and to help build up, its then unique environment of intellectual and technological sophistication. There I have remained ever since.

Leveraging South African HIV research to define SARS-CoV-2 immunity triggered by sequential variants of concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has shifted our paradigms about B cell immunity and the goals of vaccination for respiratory viruses. The development of population immunity, through responses directed to highly immunogenic regions of this virus, has been a strong driving force in the emergence of progressively mutated variants. This review highlights how the strength of the existing global virology and immunology networks built for HIV vaccine research enabled rapid adaptation of techniques, assays, and skill sets, to expeditiously respond to the SARS-CoV-2 pandemic. Allying real-time genomic surveillance to immunological platforms enabled the characterization of immune responses elicited by infection with distinct variants, in sequential epidemic waves, as well as studies of vaccination and hybrid immunity (combination of infection- and vaccination-induced immunity). These studies have shown that consecutive variants of concern have steadily diminished the ability of vaccines to prevent infection, but that increasing levels of hybrid immunity result in higher frequencies of cross-reactive responses. Ultimately, this rapid pivot from HIV to SARS-CoV-2 enabled a depth of understanding of the SARS-CoV-2 antigenic vulnerabilities as population immunity expanded and diversified, providing key insights for future responses to the SARS-CoV-2 pandemic.

Population Immunity and Covid-19 Severity with Omicron Variant in South Africa.

BACKGROUND: The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified on November 25, 2021, in Gauteng province, South Africa. Data regarding the seroprevalence of SARS-CoV-2 IgG in Gauteng before the fourth wave of coronavirus disease 2019 (Covid-19), in which the omicron variant was dominant, are needed. METHODS: We conducted a seroepidemiologic survey from October 22 to December 9, 2021, in Gauteng to determine the seroprevalence of SARS-CoV-2 IgG. Households included in a previous seroepidemiologic survey (conducted from November 2020 to January 2021) were contacted; to account for changes in the survey population, there was a 10% increase in the households contacted, with the use of the same sampling framework. Dried-blood-spot samples were tested for IgG against SARS-CoV-2 spike protein and nucleocapsid protein with the use of quantitative assays. We also evaluated Covid-19 epidemiologic trends in Gauteng, including cases, hospitalizations, recorded deaths, and excess deaths from the start of the pandemic through January 12, 2022. RESULTS: Samples were obtained from 7010 participants, of whom 1319 (18.8%) had received a Covid-19 vaccine. The seroprevalence of SARS-CoV-2 IgG ranged from 56.2% (95% confidence interval [CI], 52.6 to 59.7) among children younger than 12 years of age to 79.7% (95% CI, 77.6 to 81.5) among adults older than 50 years of age. Vaccinated participants were more likely to be seropositive for SARS-CoV-2 than unvaccinated participants (93.1% vs. 68.4%). Epidemiologic data showed that the incidence of SARS-CoV-2 infection increased and subsequently declined more rapidly during the fourth wave than it had during the three previous waves. The incidence of infection was decoupled from the incidences of hospitalization, recorded death, and excess death during the fourth wave, as compared with the proportions seen during previous waves. CONCLUSIONS: Widespread underlying SARS-CoV-2 seropositivity was observed in Gauteng before the omicron-dominant wave of Covid-19. Epidemiologic data showed a decoupling of hospitalizations and deaths from infections while omicron was circulating. (Funded by the Bill and Melinda Gates Foundation.).

U-Pb-dated flowstones restrict South African early hominin record to dry climate phases.

The Cradle of Humankind (Cradle) in South Africa preserves a rich collection of fossil hominins representing Australopithecus, Paranthropus and Homo1. The ages of these fossils are contentious2-4 and have compromised the degree to which the South African hominin record can be used to test hypotheses of human evolution. However, uranium-lead (U-Pb) analyses of horizontally bedded layers of calcium carbonate (flowstone) provide a potential opportunity to obtain a robust chronology5. Flowstones are ubiquitous cave features and provide a palaeoclimatic context, because they grow only during phases of increased effective precipitation6,7, ideally in closed caves. Here we show that flowstones from eight Cradle caves date to six narrow time intervals between 3.2 and 1.3 million years ago. We use a kernel density estimate to combine 29 U-Pb ages into a single record of flowstone growth intervals. We interpret these as major wet phases, when an increased water supply, more extensive vegetation cover and at least partially closed caves allowed for undisturbed, semi-continuous growth of the flowstones. The intervening times represent substantially drier phases, during which fossils of hominins and other fossils accumulated in open caves. Fossil preservation, restricted to drier intervals, thus biases the view of hominin evolutionary history and behaviour, and places the hominins in a community of comparatively dry-adapted fauna. Although the periods of cave closure leave temporal gaps in the South African fossil record, the flowstones themselves provide valuable insights into both local and pan-African climate variability.

Human origins in a southern African palaeo-wetland and first migrations.

Anatomically modern humans originated in Africa around 200 thousand years ago (ka)1-4. Although some of the oldest skeletal remains suggest an eastern African origin2, southern Africa is home to contemporary populations that represent the earliest branch of human genetic phylogeny5,6. Here we generate, to our knowledge, the largest resource for the poorly represented and deepest-rooting maternal L0 mitochondrial DNA branch (198 new mitogenomes for a total of 1,217 mitogenomes) from contemporary southern Africans and show the geographical isolation of L0d1'2, L0k and L0g KhoeSan descendants south of the Zambezi river in Africa. By establishing mitogenomic timelines, frequencies and dispersals, we show that the L0 lineage emerged within the residual Makgadikgadi-Okavango palaeo-wetland of southern Africa7, approximately 200 ka (95% confidence interval, 240-165 ka). Genetic divergence points to a sustained 70,000-year-long existence of the L0 lineage before an out-of-homeland northeast-southwest dispersal between 130 and 110 ka. Palaeo-climate proxy and model data suggest that increased humidity opened green corridors, first to the northeast then to the southwest. Subsequent drying of the homeland corresponds to a sustained effective population size (L0k), whereas wet-dry cycles and probable adaptation to marine foraging allowed the southwestern migrants to achieve population growth (L0d1'2), as supported by extensive south-coastal archaeological evidence8-10. Taken together, we propose a southern African origin of anatomically modern humans with sustained homeland occupation before the first migrations of people that appear to have been driven by regional climate changes.

A Nanopore Sequencing-based Pharmacogenomic Panel to Personalize Tuberculosis Drug Dosing.

Rationale: Standardized dosing of antitubercular drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic assays that predict metabolism of antitubercular drugs have been lacking. Objectives: We sought to develop a Nanopore sequencing panel and validate its performance in patients with active tuberculosis (TB) to personalize treatment dosing. Methods: We developed a Nanopore sequencing panel targeting 15 SNPs in five genes affecting the metabolism of antitubercular drugs. For validation, we sequenced DNA samples (n = 48) from the 1,000 Genomes Project and compared the variant calling accuracy with that of Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n = 100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for isoniazid (INH) and rifampin (RIF). Measurements and Main Results: The pharmacogenomic panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1,000 Genomes Project. In the clinical cohort, coverage was more than 100× for 1,498 of 1,500 (99.8%) amplicons across the 100 samples. Thirty-three percent, 47%, and 20% of participants were identified as slow, intermediate, and rapid INH acetylators, respectively. INH clearance was 2.2 times higher among intermediate acetylators and 3.8 times higher among rapid acetylators, compared with slow acetylators (P < 0.0001). RIF clearance was 17.3% (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G→A substitutions (P = 0.0015). Conclusions: Targeted sequencing can enable the detection of polymorphisms that influence TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention.

Cosmogenic nuclide dating of Australopithecus at Sterkfontein, South Africa.

Sterkfontein is the most prolific single source of Australopithecus fossils, the vast majority of which were recovered from Member 4, a cave breccia now exposed by erosion and weathering at the landscape surface. A few other Australopithecus fossils, including the StW 573 skeleton, come from subterranean deposits [T. C. Partridge et al., Science 300, 607-612 (2003); R. J. Clarke, K. Kuman, J. Hum. Evol. 134, 102634 (2019)]. Here, we report a cosmogenic nuclide isochron burial date of 3.41 ± 0.11 million years (My) within the lower middle part of Member 4, and simple burial dates of 3.49 ± 0.19 My in the upper middle part of Member 4 and 3.61 ± 0.09 My in Jacovec Cavern. Together with a previously published isochron burial date of 3.67 ± 0.16 My for StW 573 [D. E. Granger et al., Nature 522, 85-88 (2015)], these results place nearly the entire Australopithecus assemblage at Sterkfontein in the mid-Pliocene, contemporaneous with Australopithecus afarensis in East Africa. Our ages for the fossil-bearing breccia in Member 4 are considerably older than the previous ages of ca. 2.1 to 2.6 My interpreted from flowstones associated with the same deposit. We show that these previously dated flowstones are stratigraphically intrusive within Member 4 and that they therefore underestimate the true age of the fossils.