In the first 6 months of the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and has infected nearly 20 million people.^1,2 As of August 10, 2020, coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, resulted in more than 163 000 deaths in the United States and more than 730 000 worldwide.² Many infected people are asymptomatic or experience mild symptoms and recover without medical intervention.^3,4 However, older people and those with comorbid hypertension, diabetes, obesity, and heart disease are at higher risk of life-threatening illness.^5,6

An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites.

Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO⁺ CD62L^- effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ⁺IL-2⁺) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field. A decade into the 21st century, malaria remains responsible for an intolerable global health burden and an effective vaccine is sorely needed. Compounding the many technical hurdles in developing such a vaccine, (naturally-acquired) immunity to malaria is generally perceived to be short-lived, although direct evidence from field studies is conflicting. To overcome this issue, we measured the development of immune responses against the malaria parasite Plasmodium falciparum in human volunteers undergoing experimental malaria infections for the first time, allowing a uniquely detailed analysis thereof. We found that cellular immune responses against two clinically-relevant life-stages of the parasite are not only rapidly acquired following even a single malaria infection, but also remain virtually undiminished over a year later – an unprecedented measurement. These findings refute conclusively the notion that an intrinsic defect exists in either the development or persistence of cellular immune responses against malaria. This realization, in conjunction with a growing recognition that such responses are indeed associated with clinical protection against malaria, markedly enhances the prospect of one day developing a successful vaccine. Simultaneously, however, these results re-focus attention on the question of why the development of long-lived immune responses is often inhibited under conditions of natural exposure.