Using initially the bacillus he had isolated in Santos and improving the known methods, Oswaldo Cruz managed to get the newly created Institute to produce, just six months after its foundation, a vaccine and a serum, which would soon be recognized internationally as excellent (according to Émile Roux ) and among the most effective then existing (according to W. Kolle and R. Otto, from the Institute of Infectious Diseases in Berlin - director Robert Koch). The "state of the art" in this regard was exposed in an extensive article in Brazil-Medico in 1901, where "the arguments and facts that guided the Institute in choosing the process it adapted", the manufacturing method, the vaccination technique, the advantages of the vaccine and the care that should accompany its application.

However, the first publication of the new Institute, also in Brazil-Medico of 1901, has nothing to do with the plague, entitled "Contribution to the study of culicids in Rio de Janeiro, by Dr. Oswaldo Gonçalves Cruz (work of the Instituto of Manguinhos)". It reveals the author's nonconformity with the idea of ​​an institution merely destined for the manufacture of serums and vaccines. Less than three years ago (November 1898) the Italians Amico Bignami, Giovanni Battista Grassi and Giuseppe Bastianelli had demonstrated the transmission of malaria by anopheline mosquitoes, the Institute should therefore, in addition to the absorbing commitment it had assumed, take upon itself the task of recognizing the Brazilian representatives of this zoological group. Anopheles lutzi, a new species described in this work, is now known to occur from Amazonas to Rio Grande do Sul, and also in Bolivia, Paraguay and Argentina. This publication inaugurated the study of Brazilian medical entomology by national researchers, followed by three others, until 1907. All of them appear as works of the self-styled "Instituto de Manguinhos". In the meantime, five more contributions are published by Arthur Neiva , Carlos Chagas and Antônio Peryassú on culicids in Brazil, laying the foundations for a highly productive school of entomologists and acarologists that would develop to the present day.

The intention to make the Institute an original scientific research center that would support the applied activities is reflected in Oswaldo Cruz's publications. With the exception of two - "A vaccinação anti-pestosa" (1901) and "Dos accidentes em sorotherapia" (1902), subjects inherent to the official purpose of the institution and which appear as works of the "Instituto Sôrotherapico Federal (Instituto de Manguinhos)", all the others refer only to "Instituto de Manguinhos". Even an article on "Pest", with a broad scope (epidemiology, microbiology, transmission, symptomatology, pathological anatomy, diagnosis, treatment and prophylaxis), not dealing specifically with sera and vaccines, is "Work of the Instituto de Manguinhos". This reference continues to appear even in publications after the name change to Instituto Oswaldo Cruz.

Even during the Baron's administration as administrative director (a post he resigned in December 1902), medical students began to flock to the Institute, seeking internships or guidance for their theses, then indispensable for graduation. Other research topics were rapidly being adopted in several domains: hematology, bacteriology, protozoology, virology, immunology and helminthology. A radical change then began in the academic landscape of Rio de Janeiro: instead of the usual compilations based on current literature, monographs based on original research that only exceptionally deal with the plague appear in an increasing number. Names that would illustrate national biomedical science had their training perfected and directed under the guidance of Oswaldo Cruz at the "Instituto de Manguinhos". Among others, Carlos Chagas, Ezequiel Dias, Antônio Cardoso Fontes, Eduardo Rabello, Paulo Parreiras Horta, Henrique de Beaurepaire Aragão, Affonso MacDowell, Henrique da Rocha Lima, Raul de Almeida Magalhães, Arthur Neiva, Antônio Gonçalves Peryassú, José Gomes de Faria, Alcides Godoy , Arthur Moses to mention only the authors of some of the 23 theses produced from 1901 to 1910. The fact that this list includes not only names who joined the Institute's research staff, but also others who became prominent outside of it. in its specialties, it shows the influence of the Institute in the scientific renewal of the country.

In addition to theses, during this same phase, the Institute produces 120 original publications in national journals (the vast majority in Brazil-Medico) and in highly selective international journals, such as Centralblatt für Bakteriologie, Biologischen Zentralblatt, Archiv für Protistenkunde, Archiv für Schiffs und Tropen -Hygiene, Zeitschrift für Hygiene und Infektionskrankheiten, Münchener Medizinische, Annales de l'Institut Pasteur, Comptes Rendus de la Société de Biologie and Bulletin de la Société de Pathologie Exotique. At that time, the list of scientific journals subscribed to the Institute's Library surpassed 420 titles.