Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection with the Delta (B.1.617.2) variant: second interim results of a living systematic review and meta-analysis, 1 January to 25 August 2021

The Delta variant has become the dominant strain of SARS-CoV-2. We summarised the evidence on COVID-19 vaccine effectiveness (VE) identified in 17 studies that investigated VE against different endpoints. Pooled VE was 63.1% (95% confidence interval (CI): 40.9–76.9) against asymptomatic infection, 75.7% (95% CI: 69.3–80.8) against symptomatic infection and 90.9% (95% CI: 84.5–94.7) against hospitalisation. Compared with the Alpha variant, VE against mild outcomes was reduced by 10–20%, but fully maintained against severe COVID-19.


METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
3 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

3
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

and Supplement part 3
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Supplement part 3
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
3 3 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

3-4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 4

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

5
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

5
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 5

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. Intervention: Any vaccine against COVID-19 which has been approved for use in the European Union (or will be approved soon), including complete and incomplete dosing schedules Comparators/control: placebo, no vaccination or a vaccine not directed against COVID-19 (active comparator), but also including head-to-head trials directly comparing different vaccines against COVID-19 Outcomes: 1. Efficacy and effectiveness-related outcomes: SARS-CoV2 infection (PCR-confirmed); hospitalisation due to COVID-19 (PCR-confirmed); ICU admission due to COVID-19 (PCR-confirmed); intubation and oxygen supply due to COVID-19 (PCR-confirmed); death due to COVID-19 (PCRconfirmed). 2. Safety-related outcomes: local reactions; systemic events; severe adverse events; enhanced COVID-19 disease; adverse events of special interest (AESI), including solicited and unsolicited events

S3: Search strategy
The following searches will be combined with the terms "vaccin*" and "immuniz*" and the brand names of the approved vaccines.* * For the interim analysis on effectiveness against infection with the Delta variant, the following terms were used in addition: variant*; Delta; delta; VOC*; B.1.617*

S4: Meta-analysis: Methods
Individual vaccine effectiveness estimates and confidence intervals reported in the studies were used to produce the pooled estimates. For the meta-analyses, risk ratios and their 95% confidence intervals were calculated as RR = (1-VE)/100%. Random-effects models with inverse variance weighting were applied for meta-analyses using R, metafor package. The meta-analyses were conducted stratifying the estimates by outcomes (infection (any), asymptomatic infection, symptomatic infection, hospitalisation, and severe disease).
For each outcome, random effect models were applied for vaccine-stratified subgroups of studies and all studies. The studies which did not report confidence intervals were excluded from the metaanalyses. Heterogeneity between studies was assessed using the I-square statistic. For meta-analyses based on ten or more estimates, the likelihood of publication bias was assessed by examination of funnel plots, followed by Egger's test and Begg's test.