Edouard Lhomme

Boris P Hejblum

Christine Lacabaratz

Aurélie Wiedemann

Jean-Daniel Lelièvre

Yves Levy

Rodolphe Thiébaut

Laura Richert

Analyzing cellular immunogenicity in vaccine clinical trials: a new statistical method including non-specific responses for accurate estimation of vaccine efficacy

Keywords: Flow cytometry, intracellular cytokine staining, vaccine, immunogenicity, clinical trials

methods, and so yields more detailed results and enables accurate interpretation of vaccine efficacy.

Abstract

Evaluation of immunogenicity is a key step in the clinical development of novel vaccines. Tcell responses to vaccine candidates are typically assessed by intracellular cytokine staining (ICS) using multiparametric flow cytometry. A conventional statistical approach to analyze ICS data is to compare, between vaccine regimens or between baseline and post-vaccination of the same regimen depending on the trial design, the percentages of cells producing a cytokine of interest after ex vivo stimulation of peripheral blood mononuclear cells (PBMC) with vaccine antigens, after subtracting the non-specific response (of unstimulated cells) of each sample.

Subtraction of the non-specific response is aimed at capturing the specific response to the antigen, but raises methodological issues related to measurement error and statistical power.

We describe here a new statistical approach to analyze ICS data from vaccine trials.

We propose a bivariate linear random-effect regression model for estimating the nonspecific and antigen-specific ICS responses. We benchmarked the performance of the model in terms of both bias and control of type-I and -II errors in comparison with conventional approaches, and applied it to simulated data as well as real pre-and post-vaccination data from two recent HIV vaccine trials (ANRS VRI01 in healthy volunteers and therapeutic VRI02 ANRS 149 LIGHT in HIV-infected participants).

The model was as good as the conventional approaches (with or without subtraction of the non-specific response) in all simulation scenarios in terms of statistical performance, whereas the conventional approaches did not provide robust results across all scenarios. The -We propose a new modeling approach that considers all measured data and is more flexible than conventional methods, which yields more detailed results and enables accurate interpretation of vaccine efficacy.

Introduction

In clinical development of vaccines, assessing the ability of the candidate vaccine to generate immune responses is an important objective of phase I and II clinical trials. Only candidate vaccines with sufficient immunogenicity are subjected to phase III clinical trials.

Immunogenicity can be a secondary objective of phase III vaccine trials, to investigate potential correlates of protection.

In phase I and II vaccine trials, a variety of immunological markers, including the vaccineinduced T-cell responses, are typically assayed [START_REF] Kibuuka | Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial[END_REF][START_REF] Guardo | Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization[END_REF][START_REF] Lévy | Dendritic cellbased therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load[END_REF][START_REF] Luabeya | Firstin-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults[END_REF]. T-cell responses to vaccine candidates are commonly assessed by intracellular cytokine staining (ICS), a flow cytometry assay involving cryopreserved peripheral blood mononuclear cells (PBMCs). ICS assay allows characterization of subsets of specific cytokine-producing T cells after ex vivo antigenic stimulation [START_REF] Horton | Optimization and Validation of an 8-Color Intracellular Cytokine Staining (ICS) Assay to Quantify Antigen-Specific T Cells Induced by Vaccination[END_REF][START_REF] Lin | COMPASS identifies T-cell subsets correlated with clinical outcomes[END_REF]. For example, in the case of evaluation of an HIV vaccine candidate, the cellular responses can be measured by enumerating IFNg-, IL2-, and TNFa-producing CD4+ and CD8+ T cells by flow cytometry, after stimulation of PBMCs with pools of the HIV peptides contained in the vaccine sequence, e.g., Gag, Nef, Pol, and/or Env [START_REF] Churchyard | A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204)[END_REF][START_REF] Tung | A therapeutic HIV-1 vaccine enhances anti-HIV-1 immune responses in patients under highly active antiretroviral therapy[END_REF][START_REF] Janes | Higher T-Cell Responses Induced by DNA/rAd5 HIV-1 Preventive Vaccine Are Associated With Lower HIV-1 Infection Risk in an Efficacy Trial[END_REF][START_REF] Kalams | Safety and Comparative Immunogenicity of an HIV-1 DNA Vaccine in Combination with Plasmid Interleukin 12 and Impact of Intramuscular Electroporation for Delivery[END_REF].

Different approaches exist for the statistical analysis of ICS data. Methods based on qualitative binary criteria can be used to report the proportion of vaccine recipients with a detectable or "positive" response (percentage of "responders"). The binary response variable can be defined using either empirical thresholds on a relative or absolute scale (e.g., positive response if higher than threefold the non-stimulated cells or at least 0.05% of T cells), relying on a statistical approach, or a combination of both. For instance a Fisher exact test on count data (number of flow cytometer events) is often used to compare the proportion of cytokine-producing stimulated and non-stimulated cells within a given sample, yielding a multiple testing-adjusted p-value per sample that is used as a statistical positivity criterion [START_REF] Horton | Optimization and Validation of an 8-Color Intracellular Cytokine Staining (ICS) Assay to Quantify Antigen-Specific T Cells Induced by Vaccination[END_REF]. However, in the absence of formally identified thresholds of positivity, the biological meaning of such binary criteria remains unknown. In addition, a binary variable induces a loss of precision and information and therefore decreases the statistical power compared to using the full distribution of the marker [START_REF] Richert | BiostatisticsBioinformatics Division of the ANRS Vaccine Research Institute. Is the current use of « positivity » thresholds meaningful for evaluating HIV-vaccine immunogenicity endpoints?[END_REF]. Qualitative criteria have the advantage of being easy to implement and interpret, without any positivity criteria to define. Thus, use of quantitative endpoints for the analysis of ICS responses is relevant. The gold standard (i.e., conventional statistical approaches (1-4)) for the analysis of quantitative ICS data is: i) to subtract the response observed in non-stimulated cells from each stimulated condition of a given sample and ii) to perform a standard inter-or intraarm comparison of the distribution of percentages of cells producing the cytokine(s) of interest. This can be achieved, for instance, using Student's t-test to compare two means of cytokineproducing cells at a given time point between trial arms (or for non-parametric data a rank test), or the corresponding tests for paired data for intra-group ("before-after immunization") comparisons. The background subtraction in step i) is aimed at capturing the antigen-specific response, but it can result in biased estimates and induce type-I errors (a type-I error occurs when a researcher rejects a null hypothesis when it is true), and reduce the statistical power by increasing the measurement error or biasing the observed distribution.

Moreover, although measurement errors and random biological variations are likely to contribute to the observed response in non-stimulated cells (often called "background"), it cannot be excluded that this non-specific response has some biological relevance [START_REF] Liu | High background in ELISpot assays is associated with elevated levels of immune activation in HIV-1-seronegative individuals in Nairobi[END_REF][START_REF] Su | Virus-specific CD4+ memory phenotype T cells are abundant in unexposed adults[END_REF], via bystander activation for instance, and should not be ignored in the data analysis. In addition, from a statistical point of view, the existence (or absence) of a correlation between non-specific and specific responses is significant [START_REF] Gilbert | Efficient and robust method for comparing the immunogenicity of candidate vaccines in randomized clinical trials[END_REF]. The conventional approaches do not take this into account, which may lead to erroneous results.

We propose a new statistical method for the analysis of cellular immune responses in vaccine trials using a bivariate regression model that guarantees accurate estimation of the vaccine effect.

Materials and Methods

Statistical model

We propose a bivariate linear model, which is an extension of the univariate regression models frequently used in biomedicine. While a univariate model allows estimation of the effects of one or several explanatory (independent) variables on a single response (dependent) variable, a bivariate model simultaneously includes two response markers as dependent variables [START_REF] Thiébaut | Bivariate linear mixed models using SAS proc MIXED[END_REF]. As for univariate linear regression models, a maximum-likelihood approach can be used to estimate the effects of the explanatory variables on the outcome in a bivariate model. Regression coefficients (so-called "betas") are thus estimated, along with their confidence intervals and corresponding p-values, while simultaneously modeling the vaccine effect on the non-specific and specific responses assayed by ICS.

The model considers the non-stimulated cell response and the raw stimulated cell response(s) as the dependent variables. These responses are modeled according to the vaccine effect as the main explanatory variable, and the stimulated cell response is additionally adjusted for the nonstimulated cell response. This adjustment allows consideration of the potential correlation between these responses, which is not possible with current conventional approaches. The model provides an estimation of the vaccine effect on the non-stimulated cell response and of the effect of the non-stimulated cell response on the stimulated cell response (Figure 1). The mathematical equations specifying each of the two models are described below.

Let , be the response vector for subject i, with the non-stimulated cell response, and the vector of the stimulated cell response. We define the two bivariate linear models presented above as:

Model (1) for inter-arm comparison at one time point

where is the variable indicating the vaccine arm, and and , respectively, are the parameters and the errors of the model. This formulation implies the following probability distribution for the responses and errors:

Model (2) for intra-arm comparison (post-vaccination vs. baseline)

where

) and ,! ! and are, respectively, the parameters and the errors of the model. This formulation implies the following probability distribution for the responses and errors:

# " #
We provide an implementation of the model in both SAS (using Proc Mixed) and R (using the nlme package). The SAS and R codes are provided in Appendix A. In addition, we built a user-friendly graphical interface that allows analysis of ICS data with the bivariate model and visualization of the results. The tool is implemented as an R-Shiny application and is available on the Internet (19).

Simulation study

Simulated datasets enable assessment of the performance of the proposed model in various scenarios where the truth is known (contrary to real-world data). Synthetic datasets were generated under various scenarios chosen to compare the behavior of the proposed model with the conventional approaches in different situations: a similar vaccine effect on stimulated cell response between arms to evaluate the risk of type-I error (i.e., the risk of concluding that a vaccine effect exists when it does not); the vaccine effect on the stimulated cell response to evaluate the statistical power (1-beta, or type II error); the presence and absence of correlations between the stimulated and non-stimulated responses; and with or without a vaccine effect on the non-stimulated response.

The various scenarios and parameters used to generate the data are described in Appendix B -Table 1. For each scenario, 1,000 simulations were run with three different

Results

Simulation study

The statistical performance was similar for models (1) and ( 2) in terms of control of bias, type-I error, and statistical power. A summary of the statistical performance of models ( 1) and ( 2) is shown in Figure 2 and Appendix B -Figure 1, respectively, and detailed results for model [START_REF] Kibuuka | Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial[END_REF] and model ( 2 The type-I error rate was controlled at ≈ 5% in all scenarios by the model as well as the conventional approach using the raw stimulated cell response. For the conventional method with subtraction of the non-stimulated cell response, the type-I error rate was not controlled (> 20%) when there was a vaccine effect on the non-stimulated cell response (Figure 2C, upper panel). Regarding the control of bias and statistical power (lower panel), the performance of the two conventional approaches varied across the scenarios: the raw stimulated cell response performed better than the background-subtracted response in the absence of a correlation (Figure 2A) and, more importantly, in cases of a vaccine effect on the non-stimulated cell response (Figure 2C). In contrast, a conventional approach with background subtraction was better in cases of correlations between the non-stimulated and stimulated cell responses (Figure 2 B). The proposed modeling approach had excellent performance in all scenarios, at least as good as the respective conventional approach. The exception were cases of a vaccine effect on the non-stimulated response, in which the conventional approach without backgroundsubtraction had slightly higher statistical power (Figure 2C). To have good statistical performance, a model must control the type-I error at the nominal testing level (conventionally 5%) and the power must be as high as possible.

A: Scenarios with no correlation between stimulated and non-stimulated cell response and no vaccine effect on the non-stimulated cell response B: Scenarios with correlation (p=0.70) between stimulated and non-stimulated cell response C: Scenarios with a vaccine effect on the non-stimulated cell response 3.2. Application to real-world data

VRI02 ANRS 149 LIGHT

We applied the proposed model to evaluation of cellular immunogenicity at W28 for inter-arm comparison in the vaccine and placebo arms-model ( 1)-and intra-arm comparison in the vaccine and placebo arms-model [START_REF] Guardo | Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization[END_REF]. The estimated vaccine effect on cells stimulated by Gag, Nef, and Pol/Env using models 1 and 2 and the respective conventional approaches are presented in Figure 3.

Regarding the inter-arm comparison (Figure 3A), differences were observed between the two conventional approaches: a significant change in the frequency of CD4+ T cells producing TNFα, IL2, and IFNγ in response to the Pol/Env peptide pool was found in the vaccine arm vs. the placebo arm at W28 using the approach with subtraction of the nonstimulated cell response. In contrast, the approach without subtraction found only a significant change in the frequency of CD4+ T cells producing IFNγ in response to the same peptides. The bivariate modelling approach found specific CD4+ T cells producing IL2 in response to the approach with subtraction of the non-specific response but not with the non-subtracted conventional approach. In the placebo arm (Figure 3B, lower panel), the three methods yielded discordant results. Whereas no significant CD4+ and CD8+ T-cell responses were observed with the modeling approach, several significant cellular responses were found using the conventional approaches, particularly with subtraction of the unstimulated cell response. This result may be linked to an increased frequency of type-I errors with conventional approaches.

Estimates of the vaccine effect on the non-stimulated cell response and the association of the non-stimulated response with the stimulated cell responses are shown in Appendix D. No significant vaccine effect on the non-stimulated cell response was observed with model 1 (Appendix D, Figure 1) or model 2 (Appendix D, Figure 2). However, a significant association between the non-stimulated cell response and the stimulated cell responses was found for several CD4+ and CD8+ T-cell responses in both models. For example, estimates (standard deviation) from model 1 (inter-arm comparison at W28) for the analysis of the CD4+ IL2+ response after Pol/Env stimulation were 0.010 (0.033) for the vaccine effect on the stimulated cell responses (p = 0.002), and 1.097 (0.154) for the effect of the non-stimulated response on the stimulated response (p < 0.001).

Regarding conventional approaches without subtraction, the average difference (standard deviation) in raw stimulated responses between the two arms was 0.006 (0.018) (p = 0.14; standardized effect: 0.328). With the conventional approach with subtraction of the nonstimulated response, the average difference (standard deviation) in raw stimulated responses between the two arms was 0.010 (0.014) (p = 0.003; standardized effect: 0.684). For this example, the correlation coefficient between non-stimulated response and stimulated response was 0.57, which is a moderate correlation explaining why the conventional approach with subtraction of the non-stimulated cell response was closer of the modelling result.

ANRS/INSERM VRI01

We applied the proposed model to evaluate cellular immunogenicity at W30 in the MVA-LIPO, LIPO-MVA, and GTU-MVA arms. Estimates of the vaccine effects on the Gag, Nef, and Pol/Env responses in each arm (model 2) and the respective conventional approaches are shown in Figure 4.

As expected, some discrepancies were observed between the two conventional approaches for measuring the vaccine effect. The modelling approach resolved this uncertainty, and yielded more robust results that were sometimes closer to one conventional approach, sometimes closer to the other.

Estimates of the vaccine effect on the non-stimulated response and the effect of the nonstimulated response on the stimulated responses are presented in Appendix E -Figure 1. In the analysis of VRI02 ANRS 149 LIGHT, no significant vaccine effect on non-stimulated cell responses was observed. A significant association of the non-stimulated response with the stimulated responses was found for several CD4+ and CD8+ T-cell responses.

Discussion

We present a multivariate modelling approach to analyze the cellular immune response of vaccine candidates during vaccine clinical trials. Simulations showed that the bivariate model effectively controlled the type-I error in all assessed scenarios with different population sizes, while its statistical power was at least as good as the conventional approaches in all scenarios.

Controlling type-I errors is fundamental for the consistency of research. A high frequency of type-I errors leads to an apparently statistically significant result that is not reproducible in further studies. This is one of the determinants of the very high prevalence of false-positive results [START_REF] Ioannidis | Why most discovered true associations are inflated[END_REF]. The lack of statistical power is also a drawback, especially in the context of early phase vaccine clinical trials in which the number of subjects is restricted. Conventional approaches based on comparison of the background-subtracted response by t-test are the most frequently used (1-4) but did not control type-I error and had low statistical power for the vaccine effect on the non-stimulated cell response. Comparison of the data without subtraction of the non-stimulated response exhibited little statistical power in cases of correlations between the non-stimulated and stimulated cell responses.

The use of real data from prophylactic and therapeutic HIV vaccine trials showed the feasibility of the modelling approach. Not surprisingly, divergent results among the three analysis approaches (modelling and two conventional approaches) were obtained for some ICS responses. This demonstrated that the proposed model yields robust results and provides information on the correlation between the non-stimulated and stimulated cell responses. The validity of the proposed modelling approach could not be tested with real data but an in silico study demonstrated the drawbacks of conventional methods (Gilbert et al.). The systematic use of one of the conventional approaches leads to erroneous results. The originality of our approach lies in the simultaneous modeling of the non-stimulated and stimulated responses, unlike conventional approaches. This enables assessment of the vaccine effect on stimulated cell response adjusted for the non-stimulated cell response as well as of the vaccine effect on the non-stimulated cell response without loss of statistical power. The strength of the model compared to conventional approaches is its good statistical performance irrespective of the relationship between the vaccine and the non-stimulated response and between the nonstimulated response and the stimulated response. The conventional approaches do not take these relationships into account. In addition, the bivariate model is easily extendable to multivariate models with more than two dependent variables, allowing consideration of more than one antigen, while a large number of tests must be performed using conventional approaches, leading to a risk of type-I error. Furthermore, while controlling for statistical errors, the model provides more biological information on the effect of variables on the background or on the specific response independently of the intervention. Notably, the same modelling approach can be used to explore any variable that modifies the effect of interest (e.g., the vaccine) on the ICS response. As an example, it could be used to evaluate whether the vaccine induced a similar ICS response in women and men through an interaction term.

One potential drawback of our approach is the fact that it is a fully parametric method making assumptions. It is assuming that residuals are normally (i.e., Gaussian) distributed with constant variance, which could not be the case. However, there are several arguments for thinking that the consequences on the usefulness of the method are limited. First, the conditional distribution could be more likely Gaussian than the marginal one tested with the t-test. Second, the mixed models are quite robust to misspecification of residual distribution [START_REF] Jacqmin-Gadda | Robustness of the linear mixed model to misspecified error distribution[END_REF]. Therefore, we think that parametric assumptions should not limit the use of the approach if the sample size is adequate (< 20 individuals).

Although our modeling approach is more complex than conventional approaches based on basic statistical tests (Student's t-test), this should not prevent its practical use. To facilitate its implementation, the code for SAS and R software is provided in the Appendix. In addition,

we developed an R-shiny application with an interactive and user-friendly web interface that enables immunologists to analyze their data with no statistical software or experience required.

The application provides simple and clear interpretation of the results and the output can be directly integrated into publications.

In conclusion, our novel method of analyzing T-cell immunogenicity data, based on bivariate modelling, enables consideration of all available information with more flexibility Non-stimulated response effect on stimulated response: H0 (% ' ( ≠ 0) approaches (comparing respectively the raw stimulated response or the stimulated response after subtraction of the non-stimulated response) respectively the raw stimulated response or the stimulated response after subtraction of the nonstimulated response)

-

  proposed model estimated the T-cell responses to the antigens without any effect of the nonspecific response on the specific response, irrespective of the correlation between the nonspecific and specific responses. This novel method of analyzing T-cell immunogenicity data based on bivariate modelling allows consideration of all T-cell data and is more flexible than conventional Highlight Evaluation of vaccine immunogenicity is a key step in the clinical development of vaccines; the T-cell responses to vaccine candidates are typically assessed by intracellular cytokine staining using flow cytometry. -Conventional approaches for analyzing T-cell responses can bias estimates and compromise statistical performance, particularly in terms of the type-I error rate and statistical power.

Figure 1 .

 1 Figure 1. Bivariate linear model for estimating the non-specific and antigen-specific

8 +

 8 sample sizes, respectively, 15, 30, and 60 participants per arm. Bias, type-I error control, and the statistical power of the bivariate model in each scenario were compared with those of two quantitative conventional approaches based on Student's t-test or paired t-test (for inter-and intra-arm comparisons, respectively) using (i) the raw stimulated cell response or (ii) the stimulated cell response after subtraction of the non-stimulated cell response. Relative bias was calculated as follows:where DIFFobs is the observed mean of the difference between stimulated responses (between time points in model[START_REF] Kibuuka | Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial[END_REF]; between arms in f model (2)) and DIFFtheo, the corresponding theoretical difference (known in simulations). Type-I error was calculated as the percentage of simulations with significant vaccine efficacy (p < 0.05) among scenarios with no true vaccine efficacy. Statistical power was calculated as the percentage of simulations with significant vaccine efficacy (p < 0.05) among scenarios with true vaccine efficacy. The values and parameters used to generate the unstimulated cell response and the vaccine effect were based on the magnitude of the cellular responses measured in the ANRS/INSERM VRI01 trial. All simulations were performed using SAS v. 9.4 (SAS Institute, Cary, NC).2.3.Application to real dataWe applied our modeling approach to analyze data from two HIV vaccine trials-VRI02 ANRS 149 LIGHT (NCT01492985) and ANRS/INSERM VRI01 (NCT02038842). VRI02 ANRS 149 LIGHT evaluated a prime-boost combination of DNA-GTU and Lipopeptide vaccine followed by supervised treatment interruption (STI) in a therapeutic HIV phase II randomized trial. A total of 103 HIV-1-infected participants on c-ART were randomized (2:1 ratio) to receive three doses of DNA GTU-MultiHIV B (encoding Rev, Nef, Tat, Gag, and gp160) at week (W) 0, W4 and W12 followed by two doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or a placebo. The HIVspecific CD4+ and CD8+ T-cell responses (IFNγ, IL2, TNFα) to HIV peptide pools (Gag, Nef, and Pol/Env) were assessed by ICS at W0 and W28 in 57 vaccinated and 32 placebo participants. ANRS/INSERM VRI01 was a prophylactic open-label phase I/II randomized multicenter trial of the immunogenicity and safety of three candidate vaccines used as prime or boost: MVA HIV-B (encoding Gag, Pol, and Nef); LIPO-5 (five lipopeptides from Gag, Pol, and Nef); and DNA GTU-MultiHIV B (encoding Rev, Nef, Tat, Gag, and gp160 clade B). Healthy adult volunteers were randomized to four parallel groups: G1 received MVA at W0/LIPO-5 at W20/28; G2, LIPO-5 at W0/8 + MVA at W20/28; G3, DNA at W0/4/12 + LIPO-5 at W20/28; and G4, DNA at W0/4/12 + MVA at W20/28. HIV-specific CD4+ and CD8+ Tcell responses (IFNγ, IL2, TNFα) were analyzed after stimulation of PBMC by HIV antigens (Gag, Nef, and Pol/Env peptide pools) using ICS at W0, W30 and W52. Only participants from G1, G2 and G4 were included (n = 62) by ICS because frequency of W30 IFNγ-ELISpot responders was 0% in G3. Details on the ICS are provided in Appendix C. Model (1) for inter-group comparison (vaccine vs. placebo) at W28 (primary endpoint postvaccination) and model (2) for intra-group comparison (W0-W28 in the vaccine group) were applied to VRI02 ANRS 149 LIGHT ICS data. For the ANRS/INSERM VRI01 trial, only model (2) was used for intra-group comparisons (W0-W30 [primary endpoint postvaccination] in each vaccine group) as no formal comparison between vaccine regimens was planned in this trial. Each model was run for each HIV-specific CD4+ and CD8+ T-cell response (IFNγ, IL2, and TNFα) and included the non-stimulated and the three stimulation conditions (Gag, Nef, and Pol/Env) as dependent variables (i.e., a total of four response variables in the multivariate model).

  ) are provided in Appendix B (Figures 2-7 for model (1) and Figures 8-13 for model (2)).

Figure 2 :

 2 Figure 2: Evaluation of the performance of model 1 in terms of control of type 1 error and statistical power of the bivariate model for evaluating the effect of the vaccine (armvaccine versus placebo) compared to conventional approaches (with or without subtraction of the non-stimulated cell response) via simulations (1000 simulations per scenario).

  Gag peptide pool. No significant change in CD8+ T-cell responses was found with the model or the conventional approaches with and without subtraction of the non-stimulated cell response. Regarding the intra-arm comparison in the vaccine arm (Figure 3B, upper panel), the results were similar for the three methods between W0 and W28-CD8+ T-cell responses to Nef and Pol/Env and CD4+ T-cell responses to the three peptides. A significant vaccine effect on CD8+ T cells producing IL2 was detected by bivariate modelling and the conventional

Figure 3 .

 3 Figure 3. Heatmap of the p-values of the vaccine effect on the CD4+ and CD8+ T-cell responses measured by ICS in the VRI02 ANRS 149 LIGHT trial arms. The three approaches were (1) comparison of the raw stimulated cell response, (2) comparison of the specific response with subtraction of the non-stimulated cell response, and (3) a bivariate model with the non-stimulated cell responses and stimulated cell responses as dependent variables. A. Inter-arm (vaccine vs. placebo) comparisons. B. Intra-arm (week 28 vs. baseline) comparisons in the vaccine and placebo arms.

Figure 4 .

 4 Figure 4. Heatmap of the p-values of the intra-arm analysis of the vaccine effect on the CD4+ and CD8+ T-cell responses measured by ICS in the ANRS/INSERM VRI01 trial arms. The three approaches were (1) comparison of the raw stimulated response between

Model ( 2 )

 2 than conventional methods, leading to more accurate and more detailed results, enhancing interpretation of the vaccine effect on T-cell function. The use of conventional approaches, in particular comparison of the T-cell response after background subtraction, should no longer be recommended for ICS in vaccine trials. Our multivariate model is therefore an alternative to conventional approaches. The bivariate model could be used to analyze any type of functional response in which a non-stimulated cell response is measured. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/Sq7OxQ proc mixed data = DATATABLE; class ID_PATIENT STIMULATION ; model Y_d = STIMULATION STIMULATION*Y_d_NS/ cl noint; repeated /type=VC grp= STIMULATION sub= ID_PATIENT ; run ; R code Below an example of R code for a bivariate model for an inter-arm comparison at one time point post vaccination where STIMULATION is a binary variable indicating the response variable concerned (STIMULATION = 0 for Y $ %& and STIMULATION = 1 for Y $ & ); ID_PATIENT a single identification number for each patient, VACCINE a qualitative variable for the treatment group; Y_NS with Y_NS = 0 when STIMULATION = 0 and the value of the non-stimulated response when STIMULATION = 1. Model (1) nlme::gls(Y ~ -1 + STIMULATION*ARM + Y_NS, data = DATATABLE, weights = nlme::varIdent(value = c("1" = 1), form = ~ 1 | STIMULATION), method="REML" ) nlme::gls(Y_d ~ -1 + STIMULATION + Y_d_NS, data = DATATABLE, weights = nlme::varIdent(value = c("1" = 1), form = ~ 1 | STIMULATION),

modelling approach (model 2) and two conventional approaches (comparing respectively the raw stimulated response or the stimulated response after subtraction of the non-stimulated response)

modelling approach (model 1) and two conventional approaches (comparing respectively the raw stimulated response or the stimulated response after subtraction of the non-stimulated response)

Acknowledgments

The authors have no competing interests to declare. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. For this research, the SISTM team receives funding from the The Vaccine Research Institute (VRI), Laboratory of excellence supported by the Investissements d'Avenir program managed by the ANR under reference ANR-10-LABX-77-01.

Declarations of interest: none

Appendix B -Simulations

Scenarios

Appendix B -Table 1. Description of the different scenarios of simulation for Model 1 and Model 2 and parameters used for each scenario Vaccine effect on non-stimulated response:

Scenarios of simulation Hypothesis

Non-stimulated response effect on stimulated response: H0 (% * ( = 0) 0.02 0.01 ~ +(0 , 0.01) 0.04 0.01 0.01 ~ +(0 , 0.02)

Model (2), one arm comparison (post-vaccination versus baseline)

No vaccine effect Vaccine effect on stimulated response: H0

Vaccine effect on non-stimulated response: H0

Non-stimulated response effect on stimulated response: H0 (% ' ( = 0)

Vaccine effect on stimulated response, no correlation between stimulated and non-stimulated response Vaccine effect on stimulated response:

Vaccine effect on non-stimulated response: H0

Non-stimulated response effect on stimulated response: H0 (% ' ( = 0)

No vaccine effect between arms on stimulated response, correlation between stimulated and non-stimulated response Vaccine effect on stimulated response: H0

Vaccine effect on non-stimulated response: H0

Non-stimulated response effect on stimulated To have good statistical performance, a model must control the type 1 error at 5% and the power must be as high as possible (generally 80%).


History and Philosophy of Geography I: decolonising the discipline, diversifying archives and historicising radicalism

Keywords: Decoloniality, Feminism, Archives, Activism, Radicalism

, this report assesses the 'state of the art' of current attempts to make this field of studies more inclusive and to foster the increasing acknowledgement of geography's plural pasts. It does so by analysing scholarship published this year (including contributions from outside the Anglosphere), which rediscovers geographical traditions other than Northern ones, diversifies archives and places by including feminist, decolonial and subaltern outlooks, and addresses geographical traditions in radicalism and activism, increasingly connecting this field of studies with wider scholarly and political debates.

F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 'historical geography' is generally understood as a specific field addressing early transformation in given territories. Moreover, definitions such as géohistoire (French), geostoria (Italian), geohistoria (Spanish) or geo-história (Portuguese) are sometimes used to encompass the intersection of geographical and historical approaches. Therefore, in this report, I focus on scholarship addressing key questionings in the fields of philosophy and history of geography even when they are possibly labelled as 'historical geography'.

I discuss works that can foster internationalisation and inclusiveness in the discipline, identifying three main themes that emerged in the literature produced in 2019. In the first part, I address matters on decolonisation, including the rediscovery of voices and scholarly contributions from the 'Global South'. In the second part, I analyse the growing diversification of archives that is making histories of geography more international and inclusive, especially (but not exclusively) addressing feminist approaches and the rediscovery of neglected figures in disciplinary histories. In the third part, I discuss the rediscovery of notions of activism and resistance, arguing finally that, despite lingering issues, important steps are being done to increase the social and political relevance of this field of study.

Decolonising geography (and its pasts)

Plural calls to decolonise geography have been recently released with reference to both production of knowledges and inclusion of scholars from underrepresented groups (Esson et al. 2017;[START_REF] Jazeel | Mainstreaming geography's decolonial imperative[END_REF]Radcliffe 2017). In the field of the history and philosophy of geography, decolonising efforts are ongoing at several levels, including in disciplinary practices, such as the growing participation of scholars from the Global South in the international networks of historians of geography and historical geographers. At the 17 th International Conference of Historical Geographers (ICHG) held in Warsaw in 2018, it was decided for the first time to organise the next ICHG in the Global South, eventually in Rio de Janeiro in July 2021.

Moreover, an international conference for the centenary of anarchist geographer Peter Kropotkin is scheduled to take place in São Paulo in the following week, with the support of the Commission History of Geography of the International Geographical Union, to further demonstrate the importance of international networks and multilingual engagement. F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 This also corresponds to a growth in the number of journals and scholars working on geography's theories and histories in Brazil and in Latin America, and to the establishment of disciplinary networks such as the Rede Brasilis (Brazilian Network of Historical Geography and History of Geography)2 periodically organising big conferences and publishing journals such as Terra Brasilis. Two recent special issues of Terra Brasilis have been dedicated to biographies of geographers, including critical scholars and women from Latin America [START_REF] Cicalese | Elena Chiozza[END_REF][START_REF] Vargas | Graciela Uribe Ortega y la transición de la geografía mexicana[END_REF]. This interest in biographing geographers, matching international trends, includes original scholarship and translations from eminent 'Northern' scholars. As recently argued (Ferretti 2019a), this constitutes a reversal of the colonial gaze, which used to investigate the Other from the standpoint of the most powerful nations, cultures and languages. Conversely, these recent contributions seek to re-appropriate and reread in different languages (eventually Portuguese and Spanish) the classics of the discipline. A clear example of this scholarly strategy is the rubric Nossos Clásicos (Our Classics) published in each issue of the prestigious Brazilian journal Geographia, translating and commenting works from 'famous' geographers, the latest one being [START_REF] Ratzel | O espaço da vida: um estudo biogeográfico[END_REF]. These endeavours include doctoral and biographical works on European geographers whose contributions are not yet studied in their countries such as the French Camille Vallaux [START_REF] Bietti | Camille Vallaux[END_REF]. New Brazilian scholarship addresses the colonial implications of the French school of géographie humaine, traditionally very popular in Brazil, with colonial projects which had been often overlooked by French and Brazilian scholars [START_REF] Ribeiro | Geopolítica da língua francesa e colonialismo[END_REF]. All this promises further developments in the productive engagement of Latin American scholarship with philosophy and history of geography.

In Anglophone literatures, geographers increasingly recognize the need of diversifying sources and reverting predominant standpoints. An important challenge has been launched by Ruth Craggs and Hannah Neate, arguing for 'the broadening of disciplinary histories, which remain Anglo-American and exclusionary' (Craggs and Neate 2019, 1), by starting histories of (critical) geographies from the South, eventually from Nigeria. This key paper contends that research should not 'miss important contributions to the discipline and reinforce colonial-era visions of the agency and creativity of academics from the Global South' (Craggs and Neate F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 2019, 14). Craggs and Neate match scholarship which argues for paying more geographical attention to the issues of decolonisation [START_REF] Clayton | Geography and decolonisation[END_REF], increasingly including cases from areas other than the British Empire. In the Journal of Historical Geography's special issue edited by Clayton and Kumar, João Sarmento analyses the traumatisms that the decolonisation of Portuguese Africa provoked in Portuguese tropical geography by focusing on the protagonists' (mostly women) autobiographies. These recollections show how geography had anti-colonial uses in Mozambique, for instance at the occasion of 'a class discussion of Josué de Castro's book Geografia da Fome' (Sarmento 2019, 7). Materials on African decolonisation are likewise discussed by Marcus Power in his book on histories of geopolitics and development during the Cold War [START_REF] Power | Geopolitics and Development[END_REF].

Therefore, the need for rediscovering voices from the South is increasingly recognized. In 2019, new works have been published about critical and radical Brazilian geographers who were exiled or persecuted under the military dictatorship which ruled their country between 1964 and 1985, such as Josué de Castro, Manuel Correia de Andrade and Milton Santos (Davies 2019a and2019b;Ferretti 2019b and2019c). This process parallels Brazilian scholarship which is rediscovering critical and radical tendencies in disciplinary histories, although focusing on the development of these tendencies in Brazilian universities rather than in exile networks [START_REF] Lencioni | Quarante ans de géographie critique à l'USP[END_REF]. Accounting for a conference that took place at the USP in 2018, Sandra Lencioni tries to assess forty years of Brazilian critical geography, from the 1978 Fortaleza congress of the Association of Brazilian Geographers (AGB) onwards. This congress is normally considered as the foundation act of critical and radical geographies in the country, following the withdrawal of some of the most repressive laws of the military dictatorship, and the coming back from exile of key figures such as Santos. Furthermore, Portuguese scholarship acknowledges the need to rediscover the influential role of scholars outside the 'core', by arguing that authors such as Portuguese Orlando Ribeiro and Brazilian Aroldo de Azevedo appropriated originally elements from the French school rather than being merely tributaries of the North for geographical theory (Paiva and Roque de Oliveira 2019). Some interest is also rising in the neglected field of French geographers' relationship to decolonization, recently analysed by Marie-Albane de [START_REF] Suremain | Between political reserve and scientific change: French geographers and decolonisation in tropical Africa, 1945-1967[END_REF] and by Bowd and F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 Clayton in their book on French geographer Pierre Gourou and post-war tropicalism [START_REF] Bowd | Impure and Worldly Geography: Pierre Gourou and Tropicality[END_REF]. As for the former British colonies, anti-colonial authors are increasingly addressed by geographers (Davies 2019;Legg 2019b). Gerry Kearns and David Nally analyse the case of Roger Casement, whose report on Congo sake 'to make public an anticolonial epistemology' (Kearns and Nally 2019, 1), showing the possibility of 'anticolonialism at the hearth of empire' (Kearns and Nally 2019, 10). Hannah Fitzpatrick has studied the complex agencies surrounding the making of the maps used in the partition of India and Pakistan, showing heterogeneous uses of colonial and anti-colonial mappings [START_REF] Fitzpatrick | Imagining and mapping the end of an empire: Oskar Spate and the partition of India and Pakistan[END_REF]. Maps' uses and geography's performativity in nation building are likewise discussed by Róbert Győri and Charles Withers, with reference to the Trianon treaty, by mobilizing a variety of archives including manuscripts, which highlight the diversity of geography's political uses (Győri and Withers 2019).

In their book on subaltern geographies, Tariq Jazeel and Stephen Legg argue that 'critical engagements with colonialism and its afterlives are always spatial' (Jazeel and Legg 2019, 3), likewise claiming for the need of theorising from the South to rethink disciplinary (imperial) foundations. Moreover, geographers continue their critical explorations of the discipline's imperial pasts, analysing colonial fieldworks [START_REF] Michel | Making Mount Kilimanjaro German: Nation building and heroic masculinity in the colonial geographies of Hans Meyer[END_REF]) and critically scrutinising the racial discourses elaborated or accepted by early geographers for imperial purposes (Ashutosh 2019).

Critical studies are also carried out on North-American post-war neo-colonialism by authors analysing politics of expertise involving geographers (Child and Barnes 2019). Finally, matters on decolonisation are addressed both at the level of global, cosmopolitan and multilingual networking, and at the level of scholarship rediscovering different voices in anti-colonialism, de-colonisation and theorising from the South.

Diversifying voices and archives

As widely recognised, biographical and autobiographical approaches are central to the history of geography. While this is confirmed by scholarship on biogeography addressing the works of Alexander von Humboldt at the 250 th anniversary of his birth [START_REF] Schrodt | Challenges and opportunities for biogeography-What can we still learn from von Humboldt[END_REF], biographical studies do not only concern 'big men'. First, because efforts for rediscovering female figures and feminist approaches are paralleling the decolonising efforts highlighted in F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 the previous section. Second, because biographical endeavours are no longer limited to 'big' figures: as first suggested by a woman, Anne Buttimer, whose contribution is likewise being rediscovered (Ferretti 2019d;[START_REF] Jones | Anne Buttimer's The Practice of Geography: Approaching the history of geography through autobiography[END_REF]), these works also aim at unveiling stories which were previously hidden by prevailing disciplinary canons.

A good example of these processes is the latest issue of the annual publication Geographers Biobibliographical Studies which is entirely dedicated to women's biographies, a signal that was long overdue given that GBS was founded in 1977 and reaches now its 38 th volume.

Finally, the editors Elizabeth Baigent and André Reyes Novaes can now announce 'the first volume of GBS in which all subjects are female: Doreen Massey, Helen Wallis, Alice Saunier-Seïté, Isabel Margarida André, and Fanny Herbertson, Nora MacMunn, Marjorie Sweeting, Mary Marshall, Barbara Kennedy and other Oxford's women geographers' (Baigent and Novaes 2019, 1). This is especially significant if we consider that GBS is the most prestigious international series entirely dedicated to geographers' biographies, and it is edited by the IGU Commission History of Geography. This volume also has an especially high percentage of female authors (including Ana Angelita Rocha, Elizabeth Baigent, Claire Hann, Susan Squibb, Heather Viles and Sarah Tyacke), whose critical analysis is not limited to denouncing the relative paucity of women in the history of geography, as they also address the discriminations that women suffered and still suffer in terms of appointments, career advancement and work conditions. This last point is often raised by ongoing debates in feminist historical geography. Some scholars use typically historians' techniques such as autobiographical interviews to denounce everyday discriminations of women in academia [START_REF] Maddrell | Glass ceilings and stone floors: an intersectional approach to challenges UK geographers face across the career lifecycle[END_REF]. It is worth noting that feminist historical geographers are also discussing notions such as intersectionality in analysing British feminist geographers' works of the last few decades [START_REF] Evans | Feminist geography in the UK: the dialectics of womengender-feminism-intersectionality and praxis[END_REF], which means doing critical and self-reflective disciplinary historiography. Yet, it seems that many of these surveys are limited to the UK, while it would be worth further diversifying these conversations across different languages, cultures and (regional or national) institutional settings. Importantly, Briony McDonagh has defined feminist historical geographies as 'scholarship which asks geographical questions of historical F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 material and is informed by feminist theories, approaches and methodologies', one which is characterised by great diversity in its empirical approaches but mostly focuses 'on the lives of women and other marginalized groups' [START_REF] Mcdonagh | Feminist historical geographies: doing and being[END_REF](McDonagh , 1564)). The aim of extending 'feminist historiography of geography' putting it in connection with the biographical turn is expressed by Sara Albuquerque and Luciana Martins in analysing Guiana work of Hannah im to rediscover complex agencies in imperial ages (Albuquerque and Martins 2019), also recent contributions on women in the history of map-making [START_REF] Gibson | Mapmaking in home and printing house: women and cartography in late Russia[END_REF]). These works substantiate claims by Avril Maddrell for more inclusive historiographies of geography drawing upon plural feminist and critical approaches [START_REF] Maddrell | Reappraising David Livingstone's The Geographical Tradition from complex locations: More-than-contextual historiographies[END_REF]). Yet, it is not only in rediscovering feminist themes and neglected figures that histories of geography are demonstrating their diversification. It is the case with the increasingly heterogeneous archives, collections and sources that scholars mobilise. This renewed interest for archives stands in continuity with the classical works valuing contextual and space-sensitive approaches in geography's histories, on which a self-reflection has been recently launched in a themed session of Transactions of the Institute of British Geographers reassessing David Livingstone's The Geographical Tradition after its 25 th anniversary [START_REF] Boyle | Reappraising David Livingstone's The Geographical Tradition: A quarter of a century on[END_REF][START_REF] Craggs | Decolonising The Geographical Tradition[END_REF][START_REF] Meeteren | Statistics do sweat: Situated messiness and spatial science[END_REF]Ferretti 2019e;[START_REF] Livingstone | The Geographical Tradition and the challenges of geography geographized[END_REF]). In the archives, scholars are rediscovering aspects of disciplinary histories which were previously neglected such as the material circulations of objects in museums. Some of them focus on mobility and change in the field of museums and displaying, challenging more traditional readings which presumed some stability of these collections [START_REF] Cornish | Specimens Distributed[END_REF]. Collections and expositions continue to be a key part in extending and reassessing disciplinary histories including exploration, as highlighted at the occasion of a recent exhibition dedicated to Captain Cook with the aim of going beyond classical oppositions between the 'hero' and the 'villain' by discovering plural agencies in the processes of exploration [START_REF] Parker | Coming to terms with Captain Cook: exhibiting the 250th anniversary of the Endeavour voyage[END_REF].

Archives are equally revealing embodiments and materialities in knowledges' construction.

This can be exemplified by the discussions accompanying the surgencies and resurgences of scurvy in early explorers' crews, as this disease was considered as especially shameful and contradicted stereotypes of bodily discipline and performance (Armston Sheret 2019). In the F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 context of continuing geographers' engagements with wider histories of science, increasing attention is paid to archives revealing discussions on matters of scientific authority deriving from fieldwork practices. Following the example of eminent travellers such as Humboldt [START_REF] Naylor | Nineteenth-century survey sciences: enterprises, expeditions and exhibitions: introduction[END_REF], respectability came from legitimated fieldwork practices and matters of performance and skilfulness including the use of instruments. Significantly, this research is often based on the archives of the Royal Geographical Society [START_REF] Wess | Instrument provision and geographical science: the work of the Royal Geographical Society, 1830-ca 1930[END_REF]Withers 2019).

These processes of geography's professionalisation included early practices of peer-review, eventually carried out around the publications of the RGS as discussed by Benjamin Newman. The Society's archives allow understanding how the authority of the reviewers was built. They were generally not anonymous and belonged to the RGS circuits, with a quite complete 'exclusion of women' (Newman 2019, 91). The RGS archives are also the basis for original pieces of scholarship on visual cultures, including Emily Hayes's research on the use of the magic lantern at the Society's gatherings in late nineteenth century (Hayes 2019). Alongside processual archives, the Society's collections also nourish works in the history of cartography, eventually by Withers, analysing the disputes on credibility and reputation surrounding mapmaking practices in the mid-nineteenth century. These stories involved eminent Scottish mapmakers and publishers, together with a figure who had incredible international influence in the history of geography, that is German cartographer August Petermann (Withers, 2019a). These rediscoveries of archives and primary sources for empirical work is also showcased by works in cultural and historical geographies addressing different archives such as animal remaining [START_REF] Patchett | Archiving[END_REF] or imperial collections. Here, the archives are not only used as sources for the history of geography: there is also an emphasis on how they were proposed and designed by colonial officers (including geographers), like in the case of the India Office archive [START_REF] Mitchell | The centre of the muniment: archival order and historiography in the India Office, 1875[END_REF]. Histories of geographical ideas likewise focus on popular outputs as showed by scholarship on the idea of 'effective settlement' in North America [START_REF] Meyer | First effective settlement: Histories of an idea[END_REF]). Therefore, it is possible to argue that the diversification of archives and voices is enlarging our understanding of geography's plural pasts, which include activism and radicalism as I discuss in the next section. F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442

Historicising radicalism (and rediscovering activism)

In the last few years, scholars have started what might be defined a historicization of the rising of 'radical geographies' from the 1960s and 1970s. Lives and works of key exponents of this movement, such as (among others) William Bunge, Neil Smith and Milton Santos have started to be addressed, together with works on concurrent phenomena such as the 'quantitative revolution' in geography [START_REF] Barnes | The odd couple: Richard Hartshorne and William Bunge[END_REF][START_REF] Mitchell | Smith, 1954-2012: Marxist Geographer[END_REF]. In Barcelona, Abel Albet and Núria Benach are editing a collection, Espacios Críticos, where biographies and chosen texts from key figures of critical and radical geographers are translated into Spanish and discussed. A book recently co-edited by Trevor Barnes and Eric Sheppard, Spatial Histories of Radical Geography, clearly represents an international milestone in this process. In the introduction, the editors declare their aim of deconstructing 'the Clark University-centered history of Anglophone North American radical geography' and of providing 'selected samples beyond the core' (Barnes and Sheppard 2019, xix). Yet, in this book, the relation between North America and the 'rest' remains asymmetric, and the most original pieces of scholarship can accordingly be found in the chapters associated with the English-speaking circuits, which have anyway the big merit of analysing places, networks and movements of radical geographies beyond North-American universities, including the British ones [START_REF] Norcup | Let's here [sic] it for the Brits, You help us here' 1: North American Radical Geography and British Radical Geography Education[END_REF]. Some chapters of this book engage with archives and interviews with protagonists, many of whom witness limits and contradictions of the 'radical geography' movement, including the attitudes of some of its eminent exponents. Some of them fostered 'a narrow, masculinist interpretation of Marxism' (Huber, Knudson and Tapp 2019, 104), being 'the key theorists all white men' (Barnes and Sheppard 2019, 18). In the same vein, Audrey Kobayashi notices a lack of connection between radicalism, anti-colonialism and critical race studies which left 'many of the geographers of color out of the picture' (Kobayashi 2019, 40). In terms of effective critiques to Euro-centric thinking, Kobayashi identifies an important exception in Jim Blaut's work, which remains relatively understudied.

3 https://www.icariaeditorial.com/archivo/coleccion_detallada.php?id=41 F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442

The complex links between radicalism and activism are showcased in the history of the Union of Socialist Geographers (Peake 2019), while other unorthodox tendencies within the critical movements that challenged spatial science are also considered to be: Porter's anti-colonial development work in Africa, and Yi-Fu Tuan's alternative "humanistic geography"' (Lauria et al. 2019, 249). Some chapters of the book tell less-known stories like the establishment of radical groups in the Midwest, eventually at Madison, following a Bunge's visit and including student activism. This is one of the rare points where anarchism is showcased in this book, by mentioning discussions on Kropotkin, and one 'Elisée Reclus Geography Club' (Lauria et al. 2019, 261) promoted there by Kent Mathewson. Activism was displayed in anti-war mobilisations over Vietnam, involving scholars such as Marshall Sahlins from the 1960s (Lauria et al. 2019, 264). Even though this book includes chapters discussing radical geographies (or their possible absence) in Japan, Mexico, France and South Africa, one can argue that rediscoveries of critical and radical traditions beyond the North and the Anglosphere are just starting, as suggested by the works on Brazilian scholars mentioned above.

These works are inserted in the wider context of the rediscovery of radicalism and activism, including scholarship in historical geography analysing global networks of subaltern and decolonial solidarity 'from below' (Featherstone 2019a, 539). Among these authors, Christopher Hill argues for reading archives of international post-war pacifist action against the establishment of nuclear devices (in Germany and Ghana) as alternative and nonviolent geopolitics explicitly associated with the notion of activism [START_REF] Hill | The activist as geographer: nonviolent direct action in Cold War Germany and postcolonial Ghana, 1959-1960[END_REF]. Likewise, for the postwar period, Jake Hodder reconstructs Martin Luther King's readings and appropriations of Gandhi's legacy as a contribution to critical geographies of race [START_REF] Hodder | Casting a black Gandhi: Martin Luther King Jr., American pacifists and the global dynamics of race[END_REF]. In geographical theory, Legg joins ongoing conversations on Foucault's possible contributions to activism, discussing his ideas on resistance (Legg 2019). This complements recent contributions on subaltern geography, eventually Jazeel's and Legg's book, which includes several historically-driven chapters, arguing for 'tracing the relations between subaltern studies and diverse articulations of … world histories from below' (Featherstone 2019b, 95). Among other contributions explicitly targeting geography's decolonisation, Jo Sharp addresses the involvement of professional geographers from the F. Ferretti, 2019 "History and Philosophy of geography I: decolonising the discipline, diversifying archives and historicising radicalism", Progress in Human Geography, DOI: 10.1177/0309132519893442 Global North in initiatives for decolonisation such as the University of Dar es Salaam in the 1960s and 1970s [START_REF] Sharp | Practicing Subalternity? Nyerere's Tanzania, the Dar School, and Postcolonial Geopolitical Imaginations[END_REF]. Francophone geography is likewise contributing to rediscovering engaged geographies by analysing archives of scholars facing Nazi occupation during the Second World War [START_REF] Ginsburger | De Louis-le-Grand à Radio-Paris: l'inspecteur général et géographe Henri Boucau et ses collègues entre le régime de Vichy et l'épuration[END_REF]) and histories of early anarchist recently discussed in relation to anthropological sciences [START_REF] Pelletier | Une géographie et une anthropologie anarchistes[END_REF]). Finally, it can be argued that this literature, and the wider geographers' participation in initiatives such as 'Archiving Activism', 4 demonstrate the increasing importance of radicalism and activism in the field of philosophy and history of geography, one which is growingly connected with wider debates on critical geographies, decoloniality and social movements.

Conclusion

It is possible to conclude that scholarship in the history and philosophy of geography (and related fields) is increasingly plural and inclusive and willing to develop networking worldwide, paying increasing attention to different geographical traditions, sources, authors and places of production of knowledge that were not always canonised by prevailing disciplinary tendencies. Yet, there are still challenges, such as the permanence of monolingual habits, not only in English-speaking scholarship, but also in other circuits such as the Francophone and the Lusophone ones.

Even on themes such as radical and subaltern geographies, authors and topics remain for the majority Northern and English-speaking. Yet, while the need for cosmopolitan openings is increasingly recognised, these limitations are not to undermine the importance of the engagement of authors in historical-geographical fields with activism, radicalism, feminism, subaltern studies and 'voices from the Souths'. To come back to the starting question, much work is still needed to increase the inclusiveness of history and philosophy of geography, but important steps have been done and important premises have been put in place to foster the social and political relevance of this field of studies.

There are some exceptions: for instance, at the RGS-IBG there are two different research groups for these specialities, the HGRG and the HPGRG.

See the groups' website: http://redebrasilis.net/