key: cord-1044042-ivm2clf7
authors: Rose, S. M.; Schmit, V. L.; Darton, T. C.; Eyal, N.; Magalhaes, M.; Morrison, J.; Peeler, M.; Shah, S. K.; Marsh, A. A.
title: Characterizing altruistic motivation in potential volunteers for SARS-CoV-2 challenge trials
date: 2021-03-17
journal: nan
DOI: 10.1101/2021.03.14.21253548
sha: 8882cd30c8627f1d85ec32529a00c32c3181593e
doc_id: 1044042
cord_uid: ivm2clf7

In human challenge trials, volunteers are deliberately infected with a pathogen to accelerate vaccine development and answer key scientific questions. In the U.S., preparations for challenge trials with the novel coronavirus are complete, and in the U.K., challenge trials have recently begun. However, ethical concerns have been raised about the potential for invalid consent or exploitation. These concerns largely reflect worries that challenge trial volunteers may be unusually risk-seeking or too economically vulnerable to refuse the payments these trials provide, rather than being motivated primarily by altruistic goals. We conducted the first large-scale survey of intended human challenge trial volunteers and found that SARS-CoV-2 challenge trial volunteers exhibit high levels of altruistic motivations without any special indication of poor risk perception or economic vulnerability. Findings indicate that challenge trials with the novel coronavirus can attract volunteers with background conditions, attitudes, and motivations that should allay key ethical concerns.

Direct benefits to participants are not required for human subjects research to be considered 23 ethical 19 . Instead, the totality of the benefits-including benefits to others-should be sufficient 24 to justify the risks. Trials also should be designed to expose participants to as few risks as 25 possible, and participants must be able to provide valid informed consent 20 . This requires 26 providing volunteers with the opportunity to evaluate the risks, benefits, and alternatives to any 27 intervention to ensure that it reflects their goals, preferences, and values 21 . 28 Given the altruistic nature of challenge trial participation-with volunteers required to take on 29 personal risks and costs to achieve societal benefits-it would be ideal from an ethical 30 perspective if volunteers demonstrated highly altruistic goals, values and preferences. To date, 31 few studies have examined why healthy volunteers consent to research with net risks and 32 burdens to themselves, or whether their goals and values are compatible with ethical 33 participation 16, 17, 22, 23, 24, 25 . To assess whether a group of individuals who proactively declared 34 their intent to volunteer to participate in a COVID-19 challenge trial meets these conditions, we 35 conducted the first large-scale evaluation of characteristics of potential challenge trial 36 volunteers. Volunteers were recruited through the non-profit advocacy organization 1Day 37 Sooner (https://www.1daysooner.org/). 1Day Sooner was created in April 2020 to accelerate the 38 deployment of effective vaccines by supporting preparation efforts for COVID-19 challenge trials 39 and to advocate on behalf of COVID-19 human challenge trial volunteers. It curates the only 40 centralized international database of volunteers who have indicated their willingness to partake 41 in COVID-19 challenge trials. 42 We hypothesized that COVID-19 challenge trial volunteerism reflects heightened altruistic 43 values and preferences. In light of concerns that challenge trials may attract participants who 44 are unusually insensitive to risk or who are in dire economic need 10, 11, 17 , we also tested the 45 alternate hypotheses that challenge trials attract participants who engage in elevated risk 46 behaviors (including specifically health and safety related risk behaviors) or those who are 47 economically or otherwise vulnerable to exploitation. Either of these issues could raise concerns 48 about the ethical permissibility of trials, although trialists could still try to select for those 49 intended volunteers who have accurate risk perceptions and no socioeconomic motivations. 50

To test these hypotheses, we conducted a pre-registered (https://osf.io/fqyrb) study in which we 51 measured altruistic motivation, values, and behavior; risk preferences and behaviors, and 52 sociodemographic variables in 1,911 potential COVID-19 challenge trial volunteers. We 53 compared volunteers to 999 controls recruited to reflect approximate 2019 US Census 54 demographics, whose characteristics are described in Table 1 . 55

Most volunteers (66.2%) were between 18 and 45 years of age, identified as non-Hispanic white 58 (78.5%), and had a bachelor's degree or higher (77.4%). A majority reported residing in the 59 United States (81.5%), followed by Canada (7.6%), the United Kingdom (2.3%) and Germany 60 (1.0%). Most volunteers had either private health insurance or access to healthcare through 61 publicly-funded health systems (88.1%). Approximately one in three volunteers (32.0%) lived 62 alone, and a similar proportion (34.4%) lived with only one other person. 28 .7% of volunteers 63 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 17, 2021. ;  https://doi.org/10.1101/2021.03.14.21253548 doi: medRxiv preprint had at least one child. Half of volunteers were employed full-time (50.8%) and most (71.9%) 64

reported an annual household income greater than US $50,000. Of the total, 213 reported an 65 annual household income less than US $25,000 (see Table 1 

Following our pre-registered analysis plan, we conducted an exploratory factor analysis on 79 responses to the 10 motivations for volunteering (see Supplementary Information) , which 80 returned a three factor solution, with one factor comprising the two altruistic motivations. The 81 percentages of participants who selected each of the motivations were calculated ( Table 2 ). The 82 two altruistic motivations were the only options selected by majorities of respondents; both were 83 selected by over three-quarters of volunteers ("I wanted to help others and potentially save 84 lives" (95.9%) and "I wanted to contribute to the progress of medicine" (79.2%)). The third most 85 highly ranked choice ("I feel helpless and this is a way to do something positive" (46.6%)) was 86 selected by a minority of volunteers, as were the remaining options. 87 88 We next conducted chi-square tests to compare challenge trial volunteers' and controls' prior 89 engagement in altruistic behavior and found that volunteers were more likely than controls to 90 have participated in all but one of these behaviors ( Figure 1 indicating that the addition of demographic covariates improved the fit of the model overall. 136

We next compared risk behaviors and evaluations across the two groups. We predicted that 138 volunteers would not, in general, exhibit more risk-taking behaviors or risk insensitivity relative 139 to controls 29 . We compared groups on the six DOSPERT risk domains for each of the three 140 components using an ANCOVA model (Table 6 and Supplemental Table 3 and 4), which 141 included an additional covariate for age, and included the categorical variables of income, 142 education level, gender, and US residency as fixed effects to control for the potential role of 143 demographic differences between volunteers and controls. Results indicated that volunteers 144 differed from controls in risk-taking attitudes in all domains. However, the volunteer group was 145 not consistently the more risk-seeking group. Relative to controls, volunteers demonstrated 146 greater risk-aversion in the domains of ethics, gambling, and health and safety. This effect was 147 greatest for risk aversion relating to ethical (V: 1.73, C: 2.60, p<0.001, η 2 =0.113) and financial-148 gambling scenarios (V: 1.40, C: 2.45, p<0.001,η 2 =0.107). By contrast, volunteers were more 149 risk-seeking than controls with respect to financial investing, recreational activities, and social 150 behaviors (for example, challenging norms or authority). The effect size of risk-seeking was 151 greatest within the social domain (V: 5.39, C: 4.40, p<0.001,η 2 =0.126). Other dimensions of risk-152 taking showed small differences across the groups (η 2 =0.004-0.028). 153 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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We also identified significant differences between volunteers and controls on the risk-perception 154 component of the DOSPERT across all domains, with the exception of the ethical domain. The 155 strengths of associations were mostly small or trivial (η 2 <0.01-0.06). However, medium effects 156 were observed for the perception of social risk, which was greater in controls than volunteers (V: 157 2.71, C: 3.47, p < 0.001, η 2 = 0.08). Finally, with respect to the perceived-benefits scale of the 158 DOSPERT, volunteers perceived risk-taking behaviors in the ethical (V: 2.04, C: 2.83, p < 159 0.001, η 2 = 0.085), financial-gambling (V: 2.04, C: 3.03, p < 0.001, η 2 = 0.081) and health and 160 safety domains (V: 1.80, C: 2.48, p < 0.001, η 2 = 0.084) as significantly less beneficial than did 161 controls (all medium effect sizes). Exceptions included the recreational (V: 3.27, C: 3.02, p < 162 0.001,η 2 = 0.006) and social domains (V: 4.37, C: 3.94, p < 0.001,η 2 = 0.025), which volunteers 163 perceived as more beneficial than did controls (although differences had trivial and small effect 164 sizes, respectively). 165

Further analyses regarding risk-perception relating to COVID-19 and challenge trial participation 166 identified in the pre-registration plan were beyond the scope of this paper and will be discussed 167 in forthcoming papers. 168

Together, these results indicate that the characteristics of volunteers for COVID-19 challenge 170 trials do not substantiate concerns regarding understanding, vulnerability, or undue influence. 171

Volunteerism was overwhelmingly associated with heightened altruistic motivation and behavior. 172

Nearly all volunteers reported altruistic motivations for volunteering, and demonstrated high 173 levels of prior engagement in other forms of altruism, including donating blood, donating money 174 to charity, and registering as living marrow donors and deceased organ donors. Volunteers also 175 scored higher in personality traits like Honesty-Humility that reflect high valuation of others 176 relative to the self 30 . Together, these metrics suggest that those who volunteer to participate in 177 COVID-19 human challenge trials (the benefits of which primarily accrue to others) exhibit 178 reliably altruistic motivations, preferences, and values consistent with the goals of these trials. 179

We did not find evidence that challenge trial volunteerism is disproportionately associated with 180 psychological or demographic factors that might raise ethical concerns. Comparing risk 181 perceptions and behaviors between volunteers and controls, we found that group differences 182 were generally small in magnitude and did not suggest that volunteers were generally 183 insensitive to factors that compromise physical health or safety. Although volunteers indicated 184 that they would be more likely than controls to take risks in social, recreational, and investment 185 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 17, 2021. ; https://doi.org/10.1101/2021.03.14.21253548 doi: medRxiv preprint domains, they indicated being less likely to take risks in the health and safety domain. Group 186 differences in ratings may reflect in part the different risk/benefit profiles that the two groups 187 perceived for different categories of risk. Volunteers perceived slightly lower risks in the health 188 and safety domain than controls (η 2 =0.003), but also perceived lower benefits to activities in that 189 domain (η 2 =0.087). 190

We also found no evidence that volunteerism is associated with high levels of socioeconomic 191 vulnerability that might make volunteers subject to exploitation. Due to the lengthy quarantine 192 period required in COVID-19 challenge trials, the recently approved U.K. trial will compensate 193 volunteers £1,500 for a 17-day quarantine. We cannot rule out the possibility that this payment, 194 meant to compensate for quarantine only, may nonetheless attract people seeking economic 195 gain, which might be construed as coercion or undue inducement to participate (see Largent et 196 al 2017 31 for a review of the debate on coercion and undue inducement). Our results indicate 197 that challenge trials will likely be able to attract participants with non-economic motives. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 17, 2021. ; https://doi.org/10.1101/2021.03.14.21253548 doi: medRxiv preprint Together, these findings are inconsistent with expressed concerns that human challenge trials 219 with the novel coronavirus would be "prima facie unethical" because they would be expected to 220 follow a "pattern of exploitative recruitment" 11 . Whereas human challenge trial recruitment could 221 be viewed as inherently exploitative if it attracted volunteers who find participation "very 222 attractive as a result of being in a socioeconomically disadvantaged position as a result of social 223 injustice" 11 or whose volunteerism reflects "financial desperation, or a distorted understanding of 224 the risks" 38 Nor can we rule out, based on our data, the possibility that challenge trial volunteerism reflects 240 unmeasured biases related to the perception of risks and benefits, such as optimism bias 10, 40 ; 241 the so-called preventative or therapeutic fallacy, which reflects a common assumption that any 242 treatment offered by medical professionals must be potentially beneficial 41, 42 ; or unrealistic 243 beliefs about potential personal gains. To some degree, such concerns can be resolved through 244 a robust informed consent process 16, 17, 43 , which is broadly viewed as possible for COVID-19 245 challenge trials 2, 33, 44, 45, 46 . If, as our findings suggest, intended COVID-19 challenge trial 246 volunteers are mostly aware of and prepared to take the personal risks associated with such 247 studies to benefit the greater good, then, given the large number of intended volunteers to come 248 forth in a short amount of time, we can expect that there will be a sufficient number of altruistic 249 volunteers able to provide valid consent to make these trials both ethical and feasible. 250 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted March 17, 2021. ; https://doi.org/10.1101/2021.03.14.21253548 doi: medRxiv preprint were filtered if they responded in a language other than English, or if responses were too brief 287 (<5 words) to ascertain fluency in English. All participants who completed the survey were 288 compensated $5 USD in the form of an electronic gift card. Participants who expressed interest 289 in completing the survey were allotted 7 days to complete it at a time of their choosing, and 290 could complete it in more than one sitting if they preferred. Those who did not complete the 291 survey were sent follow-up emails on Day 4 and Day 6 to give them the opportunity to complete 292 their response. The protocol was approved by the Institutional Review Board at Rutgers 293 University (Study ID: Pro2020001023) and all participants provided electronic informed consent 294 before beginning the survey. All statistical tests for this study were taken from the same sample 295 and are two-tailed tests. 296

Indices of altruistic values and preferences were as follows: First, the volunteer group selected 298 their top three motivations for volunteering from a list of 10 possible motivations drawn from 299 consultations with a panel of challenge study researchers and bioethicists ( Table 2 ) (controls did 300 not complete this section) 16, 18, 25, 51 . Two motivations were primarily altruistic in that they refer to 301 outcomes for entities outside the self ("I wanted to help others and potentially save lives" and "I 302 wanted to contribute to the progress of medicine"); the other 8 reflected various other 303 motivations (e.g., "I wanted to receive the financial reimbursement for participating" or "I was 304 curious about COVID-19"). Second, participants indicated their prior engagement in various 305 altruistic behaviors that carry varying levels of risk and cost, including blood donation, 306 registering to donate bone marrow, registering to be a deceased organ donor, donating money 307 to charity, and living organ donation. Participants completed two additional instruments 308 assessing personality traits and risk perception. The Brief HEXACO inventory is a 24-item 309 measure assessing six dimensions of personality: Honesty-Humility, Emotionality, eXtraversion, 310

Agreeableness, Conscientiousness, and Openness to Experience 52,53 . Each item is rated on a 311 five-point scale. Unlike five-factor inventories, HEXACO inventories include a subscale 312 (Honesty-Humility) that specifically indexes attitudes and behaviors related to valuation of 313 outcomes for others versus the self (such as exploitation, manipulation, or deceit) and has been 314 consistently linked to prosocial motivation and behavior 30, 54, 55 . The DOSPERT scale is a 30-item 315 index that assesses three primary components of risk attitudes (risk-taking, risk-perception and 316 perceived expected benefits) across six broad decision categories: ethical, financial (divided into 317 investment and gambling), health and safety, social, and recreational risks 56 . The risk-taking 318 scale assesses respondents' likelihood of engaging in the risky activity or behavior, the risk-319 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 17, 2021. ; https://doi.org/10.1101/2021.03.14.21253548 doi: medRxiv preprint perception scale assesses how risky participants perceive each of these activities to be, and the 320 expected-benefits scale assesses how beneficial participants perceive each activity to be. 321

Responses are made using a 7-point scale (1 = Extremely unlikely/Not at all risky/No benefits at 322 all, 7 = Extremely likely/ Extremely risky/Great benefits). Finally, all participants completed an 323 assessment of socioeconomic and other demographic variables (see Table 1 for a description of 324 these demographic characteristics). Regression models for all analyses included the covariates 325 of age, gender, education level, income and country of residence to control for the potential 326 influence of differences in these characteristics. Age was included as a continuous (scale) Table 2 for a comparison of the HEXACO dimensions and Survey EFA components by 340 question). Therefore, subsequent analyses were performed using the standard six HEXACO 341 dimensions. Firstly, scores on each HEXACO dimension were compared across volunteer and 342 control groups using an ANCOVA model controlling for age, income, education level, country of 343 residence and gender. Subsequent analyses were conducted to determine the likelihood of 344 participants being in the volunteer or control group based on their HEXACO scores. These 345 analyses were initially conducted using a multivariate logistic regression containing only the six 346 HEXACO dimensions as independent variables, and membership in the volunteer group as the 347 dependent variable. An additional multivariate analysis including the demographic covariates of 348 age, gender, education level, income, and US residency was then conducted. 349 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. were compared across the volunteer and control groups using an ANCOVA model that included 359 an additional covariate for age, and included the categorical variables of income, education level, 360 gender, and country of residence as fixed effects to control for the potential role of demographic 361 differences between volunteers and controls. 362

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