including yellow fever, polio, diphtheria, rubella, smallpox, mumps, and measles in humans; and equine infectious anemia, classic swine fever, and cattle plague in animals. The successful prevention of these diseases has saved millions of lives, as well as time and efforts in health care. However, conventional vaccines are usually not effective as therapeutic measures, and often fail to provide sufficient protections against some diseases. Therefore, many major diseases, such as the malaria, tuberculosis, dengue, human immunodeficiency virus (HIV) infections, and cancer, still lack effective vaccines, and developing vaccines for them remains challenging. [5][6][7] Though many autoimmune diseases are also difficult to vaccinate, we excluded this type of diseases in the review due to their highly variable and unique mechanisms.There are various factors that may influence the outcomes of vaccines. An important discovery of modern immunology is that robust cellular immune responses with strong CD8 + T cell activities may significantly improve vaccination outcome against some of these hard-to-vaccinate diseases. This is particularly the case when the pathogens can lurk in infected cells for a long period of time (e.g., HIV) or the cells themselves became malfunctional (e.g., cancer). However, conventional vaccines often suffer from imprecise control of vaccine activity in vivo (e.g., targeted accumulation and selective cell uptake) which leads to insufficient/inappropriate immune responses or short immune memory; hence, they may become less effective in these situations. [7][8][9] Besides, rapid vaccine development, targeted epitope optimization, and other novel strategies are regarded to be important for successful prevention of infections from viral pathogens with high mutation rates (e.g., the highly variable influenza virus) which often quickly become resistant to existing vaccines. [10,11] With the advances in biological and pharmaceutical technologies, a series of new vaccines have been developed, including the famous subunit vaccines (including bioengineered protein, protein fragments, and peptides) and genetic vaccines (normally DNA-and RNA-based vaccines). These alternative vaccines provide new possibilities for preventing hard-to-vaccinate diseases by using carefully selected components of the pathogens or diseased cells as vaccine immunogens based on in-depth understanding of the immune response activation processes. More specifically, characteristic proteins/peptides Vaccination is one of the most successful and cost-effective prophylactic measures against diseases, especially infectious diseases including smallpox and polio. However, the development of effective prophylactic or therapeutic vaccines for other diseases such as cancer remains challenging. This is often due to the imprecise control of vaccine activity in vivo which leads to insufficient/inappropriate immune responses or short immune memory. The development of new vaccine types in recent decades has created the potential for improving the prot...