key: cord-0980107-k3j1v01f
authors: Preiser, Wolfgang; Fish, Therese
title: Sisonke: reaching several goals together
date: 2022-03-25
journal: The Lancet
DOI: 10.1016/s0140-6736(22)00482-2
sha: a80bb55659b9b779bc90ae155a89a9bb89bb74c5
doc_id: 980107
cord_uid: k3j1v01f

nan

Research infrastructure and expertise from decades of HIV and tuberculosis research enabled several COVID-19 vaccine trials to be conducted in South Africa. The ChAdOx1 nCoV-19 vaccine procured by the South African Government did not protect against infection with the beta (B.1.351) variant of concern 1 in a phase 1/2 trial and was therefore abandoned in early 2021. 2 A single dose of the Ad26.COV2.S vaccine had been shown to be effective against the beta variant of SARS-CoV-2 by the ENSEMBLE trial, 3 but as of early 2021 it was not yet authorised by the national regulator. Thus, South Africa found itself without a licensed and available SARS-CoV-2 vaccine. 4 The Sisonke ("We are together" in isiXhosa) open-label, phase 3b, implementation study, which is reported in The Lancet by Linda-Gail Bekker and colleagues, 5 stepped in. Offering the single-dose Ad26.COV2.S vaccine Sisonke: reaching several goals together device in patients at the highest tertile of right atrial volume, as well as those with significant pulmonary hypertension during exercise. A differential effect of shunt device treatment was seen between men and women (p interaction =0·02), with women potentially deriving more benefit from shunt placement than men. These groups that did not have a benefit probably draw the summary effect toward the null and, although they should only be considered hypothesis generating, might offer important insights into who should (or should not) be enrolled in future trials. Additionally, specific attention is required to long-term outcomes of risk, including worsening right heart failure, ischaemic stroke, and the potential for device-related events, especially given the signal for excess major cardiac events seen within the first year in this study.

It is worth remembering that despite the overall absence of improvement with this device, we now have new pharmacological options for heart failure. Sodiumglucose co-transporter 2 inhibitors reduce heart failurerelated admissions to hospital and improve morbidity across the heart failure spectrum, including in heart failure with preserved ejection fraction. 6, 7 Similarly, sacubitril-valsartan might benefit certain patients with heart failure and preserved ejection fraction, particularly women and those with mildly reduced LVEF. 8 Future studies of device therapy for heart failure and preserved ejection fraction should strive to maximise use of these medications.

The field of interatrial shunt technologies now includes novel designs with customisable aperture sizes and new approaches that do not require permanent device implantation after creation of an interatrial shunt. Although the findings of the REDUCE LAP-HF II trial are neutral, the authors have generated novel and necessary insight to advance the field by potentially answering pertinent questions, such as do women respond differently than men (and why)? What are the optimal haemodynamic criteria (such as pulmonary vascular resistance values or right-to-left pressure gradients) to study? And, what is the best assessment to exclude significant right heart failure? In answering these questions, we can hopefully determine whether the future armamentarium of heart failure therapies should include interatrial shunts and identify the correct population likely to benefit from this innovative approach.

We declare no competing interests. (Johnson & Johnson) to volunteer health-care workers, the Sisonke study not only yielded important real-life vaccine effectiveness data but also enabled South Africa to start vaccinating an important risk group. 6 In the Sisonke study, 5 122 vaccination sites recruited 477 102 health-care workers, of whom 75% were female, including 39 383 individuals known to have HIV. Recruitment spanned mid-February to mid-May, 2021, a period during which the delta (B.1.617.2) variant of concern replaced the beta variant and drove South Africa's third COVID-19 epidemiological wave. 7 Overall, vaccine effectiveness from 4 weeks after vaccination was 83% (95% CI 75-89) to prevent COVID-19-related death, 75% (69-82) to prevent COVID-19related hospitalisation requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisation. Importantly, vaccine effectiveness was reduced but maintained in participants older than 50 years and those with self-reported HIV infection and other comorbidities, and throughout the periods dominated by both the beta and delta variants.

The Sisonke study's strength is that it provided realworld evidence in a highly exposed population with a substantial proportion of HIV-infected individuals. Furthermore, it enabled health-care workers, who have a high risk of infection and are an essential workforce, especially during pandemic waves, to be vaccinated ahead of the national programme.

The pandemic has substantially affected the education of future health professionals because teaching had to be done online and in-clinic training was halted. Additionally, health services focused on COVID-19 care, with all elective and non-emergency care de-escalated.

Participation in the Sisonke trial put minimal additional demands on participants, but yielded important data on vaccine effectiveness and safety in real life, including groups who are under-represented in most vaccine trials. It employed South Africa's then newly launched national electronic vaccination data system, which was then also used for the governmental vaccine roll-out programme.

The broad definition of health-care worker used in the Sisonke study, including students and auxiliary staff not exposed to patients, did not allow prioritisation according to risk category. 8, 9 Although the single-dose Ad26.COV2.S vaccine was effective against severe COVID-19 caused both by beta and delta variants of SARS-CoV-2, the short followup period reported here did not allow assessment of the duration of protection, nor did the reported study period include the emergence of the omicron (B.1.1.529) variant of concern in South Africa from November, 2021. 10 Breakthrough infections with omicron in Sisonke participants have been published in the meantime in a preprint publication. 11 As per the interim recommendations of WHO's Strategic Advisory Group of Experts on Immunization, a single dose of Ad26.COV.2 does not provide long-lasting reliable immunity. 11 Through Sisonke2, a follow-on trial of Sisonke, over 230 000 participants of the first Sisonke trial received a second Ad26.COV.2 dose, which was ideally timed to assess its effectiveness against the omicron variant, and has been reported in another preprint publication. 12 Some health-care workers who did not enrol in the Sisonke study might have chosen to access the BNT162b2 (Pfizer-BioNTech) vaccine through the national roll-out programme, and those not enrolling for Sisonke2 might have opted to wait for heterologous booster doses with perceived higher efficacy. However, a substantial proportion of health-care workers in South Africa, as elsewhere, remain unvaccinated.

Open-label implementation studies allow for improved monitoring of adverse events and vaccine effectiveness compared with typical postmarketing surveillance. This type of investigation is particularly valuable when groups with unique characteristics are targeted. We believe the Sisonke study was exemplary. 

On Feb 27, 2022, Russia's President Vladimir Putin ordered Russian nuclear forces to be placed on "the special regime of combat duty". 1 This decision increased the alert status of Russian nuclear forces from a peacetime status to a pre-combat status, creating the legal conditions for any further instruction to launch missiles. Presumably Putin's move is intended to create fear and uncertainty, intensify pressure on Ukraine and the North Atlantic Treaty Organization (NATO) allies and partners, reduce resistance to Russian attacks in Ukraine, and extract concessions in negotiations. But these threats represent an absolutely unacceptable escalation of his invasion of Ukraine. The threat of nuclear weapons ratchets up tensions and increases the anxiety and stress that every soldier, resistance fighter, civilian, and politician is experiencing. This threat is also likely to affect analysis and decision making by all parties to the conflict in regard to the potentially far-reaching impacts of decisions. Indeed, history has shown us the risks that these types of situations can pose.

Since the 1960s the assumption by nuclear armed states was that the prospect of mutually assured destruction would guarantee that nuclear weapons are never used. Nuclear war was believed to be so catastrophic that no leader would ever dare use their nuclear arsenals. More recently, in January, 2022, all the nuclear weapons states that are signatories to the Nuclear Non-Proliferation Treaty (China, France, Russia, the USA, and the UK) reiterated the Reagan-Gorbachev statement that "a nuclear war cannot be won and must never be fought". 2 Nonetheless, documentary research and testimonies have revealed occasions during the decades after the Cuban missile crisis when nuclear weapons were very nearly used as a result of misperceptions and misinterpretation of signals. 3 In 1983, for example, the NATO Able Archer military exercise increased the fear level in the Soviet Union to such an extent that Russian nuclear forces were mobilised. 4 Also in 1983, satellite signals that appeared to be incoming nuclear missiles from the USA to the Soviet Union nearly led to a launch-on-warning response from Moscow. The decision not to do so rested largely on the decisions of one individual, lieutenant colonel Stanislav Petrov. 5 Even after the end of the Cold War, when tensions were low, a Norwegian rocket was initially feared to be an incoming nuclear weapons attack in Russia. 5 In the case of nuclear weapons, such mistakes, if they lead to inadvertent use, can never be small or put right. Any use of so-called tactical nuclear weapons (in the low

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

Efficacy of the ChAdOx1 nCoV-19 COVID-19 vaccine against the B.1.351 variant

Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-19

South Africa should be using all the COVID-19 vaccines available to iturgently

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study

Severe acute respiratory syndrome coronavirus 2 infection among healthcare workers in South Africa: a longitudinal cohort study

Rapid replacement of the beta variant by the delta variant in South Africa

COVID-19 mass vaccination campaign for healthcare workers in a low-resource setting: a clinician-driven initiative

Hard choices: ethical challenges in phase 1 of COVID-19 vaccine roll-out in South Africa

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

Breakthrough COVID-19 infections during periods of circulating beta, delta and omicron variants of concern, among health care workers in the Sisonke Ad26.COV2.S vaccine trial

Vaccine effectiveness against hospital admission in South African health care workers who received a homologous booster of Ad26.COV2 during an omicron COVID19 wave: preliminary results of the Sisonke 2 study